JP2016501237A - Substituted pyridopyrazine as Syk inhibitor - Google Patents

Abstract

The present invention relates to pyridopyrazine compounds of formula (I), pharmaceutical compositions thereof and therefore methods of use, wherein R1, R2, R3, L, m, p and W are as defined herein. [Selection figure] None

Description

  The present invention relates to novel pyridopyrazine compounds, pharmaceutical compositions thereof, and methods of use thereof.

  Protein kinases, the largest family of human enzymes, encompass well over 500 proteins. Spleen tyrosine kinase (Syk) is a member of the Syk family of tyrosine kinases and is a regulator of early B cell development and mature B cell activation, signal transduction, and survival.

  Syk has a variety of cells, including B cells, macrophages, monocytes, mast cells, eosinophils, basophils, neutrophils, dendritic cells, T cells, natural killer cells, platelets, and osteoclasts It is a non-receptor tyrosine kinase that plays an important role in immune receptor and integrin-mediated signaling in the form. The immunoreceptors described herein include classical immune receptors and immunoreceptor-like molecules. Classical immune receptors include B cell and T cell antigen receptors, as well as various immunoglobulin receptors (Fc receptors). Immunoreceptor-like molecules are either structurally related to the immune receptor or are involved in similar signaling pathways, such as neutrophil activation, natural killer cell recognition, and disruption. It is mainly involved in non-adaptive immune functions, including bone cell activity. Integrins are cell surface receptors that play an important role in the control of leukocyte adhesion and activation in both innate and adaptive immunity.

  Ligand binding leads to activation of both immunoreceptors and integrins, including activation of Src family kinases and the immunoreceptor tyrosine-based activation motif (ITAM) in the cytoplasmic aspect of receptor-related transmembrane adapters. Causes phosphorylation. Syk binds to the phosphorylated ITAM motif of this adapter, resulting in activation of Syk and subsequent phosphorylation and activation of downstream signaling pathways.

  Syk is essential for B cell activation through B cell receptor (BCR) signaling. SYK becomes active upon binding to phosphorylated BCR, thus initiating an early signaling event after BCR activation. B cell signaling through BCR can produce a wide range of biological outputs and thus depends on the developmental stage of the B cell. The extent and duration of the BCR signal must be accurately adjusted. Abnormal BCR-mediated signaling can lead to dysregulation of B cell activation and / or the formation of pathogenic autoantibodies, leading to multiple autoimmune and / or inflammatory diseases. Mice lacking Syk show impaired B cell maturation, reduced immunoglobulin production, an infectious T cell-independent immune response, and a marked attenuation of the sustained calcium signature upon BCR stimulation.

  Extensive evidence supports the role of the B-cell and humoral immune system in the pathogenesis of autoimmune and / or inflammatory diseases. Protein-based therapeutics developed to deplete B cells (such as Rituxan) are representative of approaches to the treatment of many autoimmune and inflammatory diseases. Autoantibodies and the immune complexes resulting therefrom are known to play a pathogenic role in autoimmune and / or inflammatory diseases. The pathogenic response to these antibodies depends on signal transduction through the Fc receptor and thus on Syk. Due to the role of Syk in B cell activation and FcR-dependent signaling, inhibitors of Syk may be useful as inhibitors of B cell mediated pathogenic activity, including autoantibody production. Thus, inhibition of Syk enzyme activity in cells has been proposed as a treatment for autoimmune diseases due to its effect on autoantibody production.

  Syk also plays an important role in FCεRI-mediated mast cell degranulation and eosinophil activation. Syk is therefore involved in allergic disorders including asthma. Syk binds to the phosphorylated gamma chain of FCεRI via its SH2 domain and is essential for downstream signaling. Syk-deficient mast cells demonstrate incomplete degranulation and the secretion of arachidonic acid and cytokines. This has also been shown for pharmacological agents that inhibit Syk activity in mast cells. Syk antisense oligonucleotides inhibit antigen-induced infiltration of eosinophils and neutrophils in animal models of asthma. Syk-deficient eosinophils also show reduced activation in response to FCεRI stimulation. Therefore, Syk small molecule inhibitors may be useful in the treatment of allergen-induced inflammatory diseases including asthma.

  Syk is also expressed in mast cells and monocytes and has been shown to be important for the function of these cells. For example, Syk deficiency in mice is accompanied by a decrease in IgE-mediated mast cell activation that causes a marked decrease in the release of TNF alpha and other inflammatory cytokines. Furthermore, Syk inhibitors have been shown to inhibit antigen-induced passive skin anaphylaxis, bronchoconstriction and bronchial edema in rats.

  Therefore, inhibition of Syk activity may include SLE, rheumatoid arthritis, multiple vasculitis, idiopathic thrombocytopenic purpura (ITP), myasthenia gravis, allergic rhinitis, chronic obstructive pulmonary disease (COPD), adult type It can be useful in the treatment of allergic disorders, autoimmune diseases and inflammatory diseases such as respiratory distress syndrome (ARD) and asthma. In addition, Syk has been reported to play an important role in ligand-independent active signaling through the B cell receptor, which is known to be an important survival signal in B cells. . Thus, inhibition of Syk activity can be useful in the treatment of certain types of cancer, including B cell lymphoma and leukemia.

  Vascular endothelial growth factor (VEGF) -A, the main regulator of angiogenesis, binds to two tyrosine kinase receptors, VEGFR-1 (Flt-1) and VEGFR-2 (KDR). Activate. VEGFR-1 (Flt-1) and VEGFR-2 (KDR) play different roles in physiological and pathological angiogenesis. VEGFR-2 (KDR) has strong tyrosine kinase activity and mainly activates MAP-kinase and DNA synthesis using the phospholipase-Cγ-protein kinase C pathway. VEGFR-2 (KDR) is a major positive signal transducer for both physiological and pathological angiogenesis, including cancer and diabetic retinopathy. Therefore, VEGFR-2 (KDR) kinase inhibitors are used in a wide range of cancer treatments. Recent studies have shown that patients are likely to require long-term treatment with these drugs. Hypertension has emerged as a frequent side effect associated with drugs that block signaling through the VEGF pathway (Pankaj Bhargava, Am. J. Physiol. Regul. Integr. Comp. Physiol. Vol. 297, R1-R5 Page, 2009). Several studies have shown that VEGF's vasodilatory and antihypertensive actions involve both receptors, but VEGFR-2 (KDR) is the dominant receptor that mediates this action. (Bing Li et al., Hypertension. 39, 1095-1100, 2002).

  Fms-like tyrosine kinase 3 (Flt-3) or the receptor tyrosine-protein kinase Flt3 (also known as the cluster of CD135, a differentiation antigen 135) is a cytokine receptor belonging to class III of receptor tyrosine kinases. is there. Flt-3 is normally expressed by hematopoietic stem / progenitor cells. Signal transduction by Flt-3 plays a role in cell survival, proliferation, and differentiation. Flt-3 is important for the development of lymphocytes (B cells and T cells), but not for the development of other blood cells (spinal cord development). Flt-3 knockout mice are very deficient in hematopoietic stem / progenitor cells. Thus, disruption targeting the Flt-3 gene results in the loss of primitive hematopoietic precursors.

  WO 2012/123312 (GLAXO GROUP) filed on March 8, 2012, entitled "Pyrido [3,4-B] pyrazine derivatives as SYK inhibitors (PYRIDO [3,4-B] PYRAZINE DERIVATIVES AS SYK INHIBITORS)" LIMITED) discloses a novel pyrido [3,4-b] pyrazine having SYK inhibitory activity.

WO 2012/123312

  At least one compound of formula (I)

及び/又はそのラセミ混合物、鏡像異性体、ジアステレオマー、互変異性体、若しくは任意の比の混合物、或いは少なくとも1つの薬学的に許容されるそれらの塩若しくは溶媒和物
[式中、
R¹は、水素、ハロ、-CN、-OH、場合により置換されているC₁〜C₆アルキル、場合により置換されているC₁〜C₆アルコキシ、-NH₂、-NH(C₁〜C₄アルキル)、及び-N(C₁〜C₄アルキル)(C₁〜C₄アルキル)から独立して選択され、
R²は、アリール又はヘテロアリール(これらの各々は、ハロ、-NR⁵R⁶、-OR⁷、-S(O)_nR⁸、-C(O)R⁹、-C(O)OR⁷、-CN、-C(O)NR⁵R⁶、-NR⁵C(O)R⁹、-NR⁵S(O)_nR⁸、-NR⁵S(O)_nNR¹⁰R¹¹、-NR⁵C(O)OR⁷、-NR⁵C(O)NR¹⁰R¹¹、-NO₂、-S(O)_nNR⁵R⁶、場合により置換されている低級アルキル、場合により置換されているシクロアルキル、場合により置換されている複素環、場合により置換されているヘテロアリール、場合により置換されているアリール、場合により置換されているアルケニル、及び場合により置換されているアルキニルから選択される1つ以上の基により場合により置換されている)であり、
Lは、結合又は場合により置換されているC₁〜C₆アルキレンであり、
Wは、シクロアルキル、複素環、アリール、又はヘテロアリールであり、
R³は、水素、-Lx-ハロ、-Lx-R⁴、-Lx-NR⁵R⁶、-Lx-OR⁷、-Lx-S(O)_nR⁸、-Lx-C(O)R⁹、-S(O)_n-Lx-R⁸、-C(O)-Lx-R⁹、-Lx-CN、-Lx-NR⁵C(O)R⁹、-Lx-NR⁵S(O)_nR⁸、-Lx-NR⁵C(O)NR¹⁰R¹¹、-Lx-NR⁵S(O)_nNR¹⁰R¹¹、-Lx-NR⁵C(O)OR⁷、-Lx-NR⁵S(O)_nOR⁷、-NO₂、-Lx-C(O)NR⁵R⁶、-Lx-S(O)_nNR⁵R⁶、オキソ(=O)、場合により置換されているシクロアルキル、場合により置換されている複素環、場合により置換されているヘテロアリール、及び場合により置換されているアリールから独立して選択されるが、
ただし、Lがメチレンであり、且つWが5員又は6員の複素環である場合、R³は、-Lx-NR⁵R⁶、-Lx-OR⁷、-Lx-S(O)_nR⁸、-Lx-C(O)R⁹、-S(O)_n-Lx-R⁸、-C(O)-Lx-R⁹、-Lx-CN、-Lx-NR⁵C(O)R⁹、-Lx-NR⁵S(O)_nR⁸、-Lx-NR⁵C(O)NR¹⁰R¹¹、-Lx-NR⁵S(O)_nNR¹⁰R¹¹、-Lx-NR⁵C(O)OR⁷、-Lx-NR⁵S(O)_nOR⁷、-NO₂、-Lx-C(O)NR⁵R⁶、-Lx-S(O)_nNR⁵R⁶、オキソ(=O)、場合により置換されているシクロアルキル、場合により置換されている複素環、場合により置換されているヘテロアリール、及び場合により置換されているアリールから独立して選択されることを条件とし、
R⁴は、C₁〜C₆アルキル、C₂〜C₆アルケニル、又はC₂〜C₆アルキニル(これらの各々は、場合により置換されている)であり、
R⁵、R⁶、R⁷、R⁸、R⁹、R¹⁰及びR¹¹は、水素、アルキル、シクロアルキル、アリール、ヘテロアリール、及び複素環(これらの各々は、水素を除いて、ハロ、-OH、-O(C₁〜C₄アルキル)、-CN、C₁〜C₄アルキル、-NH₂、-NH(C₁〜C₄アルキル)、-N(C₁〜C₄アルキル)(C₁〜C₄アルキル)、-C(O)NH₂、-C(O)NH(C₁〜C₄アルキル)、-C(O)N(C₁〜C₄アルキル)(C₁〜C₄アルキル)、-C(O)(C₁〜C₄アルキル)、-NHC(O)(C₁〜C₄アルキル)、-N(C₁〜C₄アルキル)C(O)(C₁〜C₄アルキル)、-S(O)_nNH₂、-S(O)_nNH(C₁〜C₄アルキル)、-S(O)_nN(C₁〜C₄アルキル)(C₁〜C₄アルキル)、-S(O)_n(C₁〜C₄アルキル)、-NHS(O)_n(C₁〜C₄アルキル)、-N(C₁〜C₄アルキル)S(O)_n(C₁〜C₄アルキル)、場合により置換されているC₃〜C₈シクロアルキル、及び場合により置換されている3〜8員の複素環(C₁〜C₄アルキルは、ハロ、-OH、-OMe、-CNにより場合により置換されている)から選択される1つ以上の基により場合により置換されている)から独立して選択されるか、
又はR⁵とR⁶、R⁵とR⁷、R⁵とR⁸、R⁵とR⁹、及びR⁵とR¹⁰は、それらが結合している原子と一緒になって環を形成することができ、この環は、ハロ、-OH、-O(C₁〜C₄アルキル)、-CN、C₁〜C₄アルキル、-NH₂、-NH(C₁〜C₄アルキル)、-N(C₁〜C₄アルキル)(C₁〜C₄アルキル)、-C(O)NH₂、-C(O)NH(C₁〜C₄アルキル)、-C(O)N(C₁〜C₄アルキル)(C₁〜C₄アルキル)、-C(O)(C₁〜C₄アルキル)、-NHC(O)(C₁〜C₄アルキル)、-N(C₁〜C₄アルキル)C(O)(C₁〜C₄アルキル)、-S(O)_nNH₂、-S(O)_nNH(C₁〜C₄アルキル)、-S(O)_nN(C₁〜C₄アルキル)(C₁〜C₄アルキル)、-S(O)_n(C₁〜C₄アルキル)、-NHS(O)_n(C₁〜C₄アルキル)、-N(C₁〜C₄アルキル)S(O)_n(C₁〜C₄アルキル)、場合により置換されているC₃〜C₈シクロアルキル、及び場合により置換されている3〜8員の複素環(C₁〜C₄アルキルは、ハロ、-OH、-OMe、又は-CNにより場合により置換されている)から選択される1つ以上の基により場合により置換されており、
L_xは、結合又は場合により置換されているC₁〜C₆アルキレンであり、
置換基が具体的に指定されていない、上記の場合により置換されている基の各々は、無置換とすることができるか、又は例えば、C₁〜C₄アルキル、シクロアルキル、アリール、複素環、ヘテロアリール、アリール-C₁〜C₄アルキル-、ヘテロアリール-C₁〜C₄アルキル-、C₁〜C₄ハロアルキル-、-OC₁〜C₄アルキル、-OC₁〜C₄アルキルフェニル、-C₁〜C₄アルキル-OH、-C₁〜C₄アルキル-O-C₁〜C₄アルキル、-OC₁〜C₄ハロアルキル、ハロ、-OH、-NH₂、-C₁〜C₄アルキル-NH₂、-N(C₁〜C₄アルキル)(C₁〜C₄アルキル)、-NH(C₁〜C₄アルキル)、-N(C₁〜C₄アルキル)(C₁〜C₄アルキルフェニル)、-NH(C₁〜C₄アルキルフェニル)、シアノ、ニトロ、オキソ、-CO₂H、-C(O)OC₁〜C₄アルキル、-CON(C₁〜C₄アルキル)(C₁〜C₄アルキル)、-CONH(C₁〜C₄アルキル)、-CONH₂、-NHC(O)(C₁〜C₄アルキル)、-NHC(O)(フェニル)、-N(C₁〜C₄アルキル)C(O)(C₁〜C₄アルキル)、-N(C₁〜C₄アルキル)C(O)(フェニル)、-C(O)C₁〜C₄アルキル、-C(O)(C₃〜C₈シクロアルキル)、-C(O)(C₅〜C₁₀アリール)、-C(O)(C₃〜C₈複素環)、-C(O)(C₅〜C₁₀ヘテロアリール)、-C(O)(C₁〜C₄アルキル)-(C₃〜C₈シクロアルキル)、-C(O)(C₁〜C₄アルキル)-(C₅〜C₁₀アリール)、-C(O)(C₁〜C₄アルキル)-(C₃〜C₈複素環)、-C(O)(C₁〜C₄アルキル)-(C₅〜C₁₀ヘテロアリール)、-C(O)C₁〜C₄ハロアルキル、-OC(O)C₁〜C₄アルキル、-SO₂(C₁〜C₄アルキル)、-SO₂(C₃〜C₈シクロアルキル)、-SO₂(C₅〜C₁₀アリール)、-SO₂(C₃〜C₈複素環)、-SO₂(C₅〜C₁₀ヘテロアリール)、-SO₂(C₁〜C₄アルキル)-(C₃〜C₈シクロアルキル)、-SO₂(C₁〜C₄アルキル)-(C₅〜C₁₀アリール)、-SO₂(C₁〜C₄アルキル)-(C₃〜C₈複素環)、-SO₂(C₁〜C₄アルキル)-(C₅〜C₁₀ヘテロアリール)、-SO₂(C₁〜C₄ハロアルキル)、-SO₂NH₂、-SO₂NH(C₁〜C₄アルキル)、-SO₂N(C₁〜C₄アルキル)(C₁〜C₄アルキル)、-SO₂NH(フェニル)、-SO₂N(C₁〜C₄アルキル)(フェニル)、-NHSO₂(C₁〜C₄アルキル)、-NHSO₂(フェニル)、及び-NHSO₂(C₁〜C₄ハロアルキル)から独立して選択される、1つ以上(1つ、2つ又は3つなど)の置換基により独立して置換されていることができ、アルキル、シクロアルキル、アリール、複素環、及びヘテロアリールの各々は、ハロ、シクロアルキル、複素環、C₁〜C₄アルキル、C₁〜C₄ハロアルキル-、-OC₁〜C₄アルキル、C₁〜C₄アルキル-OH、-C₁〜C₄アルキル-O-C₁〜C₄アルキル、-OC₁〜C₄ハロアルキル、シアノ、ニトロ、-NH₂、-OH、-CO₂H、-C(O)OC₁〜C₄アルキル、-CON(C₁〜C₄アルキル)(C₁〜C₄アルキル)、-CONH(C₁〜C₄アルキル)、-CONH₂、-NHC(O)(C₁〜C₄アルキル)、-N(C₁〜C₄アルキル)C(O)(C₁〜C₄アルキル)、-SO₂(C₁〜C₄アルキル)、-SO₂(フェニル)、-SO₂(C₁〜C₄ハロアルキル)、-SO₂NH₂、-SO₂NH(C₁〜C₄アルキル)、-SO₂N(C₁〜C₄アルキル)(C₁〜C₄アルキル)、-SO₂NH(フェニル)、-SO₂N(C₁〜C₄アルキル)(フェニル)、-NHSO₂(C₁〜C₄アルキル)、-N(C₁〜C₄アルキル)SO₂(C₁〜C₄アルキル)、-NHSO₂(フェニル)、-N(C₁〜C₄アルキル)SO₂(フェニル)、-NHSO₂(C₁〜C₄ハロアルキル)、及び-N(C₁〜C₄アルキル)SO₂(C₁〜C₄ハロアルキル)から選択される1つ以上の基により場合により置換されており、
mは、0、1又は2であり、
nは、1又は2であり、
pは、1、2又は3である]
が提供される。

And / or racemic mixtures, enantiomers, diastereomers, tautomers, or mixtures in any ratio, or at least one pharmaceutically acceptable salt or solvate thereof
[Where
R ¹ is hydrogen, halo, -CN, -OH, optionally C ₁ -C ₆ alkyl optionally substituted, optionally C ₁ -C ₆ alkoxy _{substituted, -NH 2, -NH (C 1} ~ C ₄ alkyl), and are independently selected from -N (C ₁ ~C ₄ alkyl) (C ₁ -C ₄ alkyl),
R ² is aryl or heteroaryl (each of which is halo, -NR ⁵ R ⁶ , -OR ⁷ , -S (O) _n R ⁸ , -C (O) R ⁹ , -C (O) OR ⁷ , -CN, -C (O) NR ⁵ R ⁶ , -NR ⁵ C (O) R ⁹ , -NR ⁵ S (O) _n R ⁸ , -NR ⁵ S (O) _n NR ¹⁰ R ¹¹ , -NR ⁵ C (O) OR ⁷ , —NR ⁵ C (O) NR ¹⁰ R ¹¹ , —NO ₂ , —S (O) _n NR ⁵ R ⁶ , optionally substituted lower alkyl, optionally substituted 1 selected from cycloalkyl, optionally substituted heterocycle, optionally substituted heteroaryl, optionally substituted aryl, optionally substituted alkenyl, and optionally substituted alkynyl. Optionally substituted by two or more groups),
L is a C ₁ -C ₆ alkylene substituted by binding or case,
W is cycloalkyl, heterocycle, aryl, or heteroaryl;
R ³ is hydrogen, -Lx-halo, -Lx-R ⁴ , -Lx-NR ⁵ R ⁶ , -Lx-OR ⁷ , -Lx-S (O) _n R ⁸ , -Lx-C (O) R ⁹ , -S (O) _n -Lx-R ⁸ , -C (O) -Lx-R ⁹ , -Lx-CN, -Lx-NR ⁵ C (O) R ⁹ , -Lx-NR ⁵ S (O ) _n R ⁸ , -Lx-NR ⁵ C (O) NR ¹⁰ R ¹¹ , -Lx-NR ⁵ S (O) _n NR ¹⁰ R ¹¹ , -Lx-NR ⁵ C (O) OR ⁷ , -Lx-NR ⁵ S (O) _n OR ⁷ , -NO ₂ , -Lx-C (O) NR ⁵ R ⁶ , -Lx-S (O) _n NR ⁵ R ⁶ , oxo (= O), optionally substituted Independently selected from cycloalkyl, optionally substituted heterocycle, optionally substituted heteroaryl, and optionally substituted aryl,
However, when L is methylene and W is a 5- or 6-membered heterocyclic ring, R ³ is -Lx-NR ⁵ R ⁶ , -Lx-OR ⁷ , -Lx-S (O) _n R ⁸ , -Lx-C (O) R ⁹ , -S (O) _n -Lx-R ⁸ , -C (O) -Lx-R ⁹ , -Lx-CN, -Lx-NR ⁵ C (O) R ⁹ , -Lx-NR ⁵ S (O) _n R ⁸ , -Lx-NR ⁵ C (O) NR ¹⁰ R ¹¹ , -Lx-NR ⁵ S (O) _n NR ¹⁰ R ¹¹ , -Lx-NR ⁵ C (O) OR ⁷ , -Lx-NR ⁵ S (O) _n OR ⁷ , -NO ₂ , -Lx-C (O) NR ⁵ R ⁶ , -Lx-S (O) _n NR ⁵ R ⁶ , oxo ( = O), optionally substituted cycloalkyl, optionally substituted heterocycle, optionally substituted heteroaryl, and optionally substituted aryl. ,
R ⁴ is C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, or C ₂ -C ₆ alkynyl, each of which is optionally substituted;
R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ and R ¹¹ are hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, and heterocycle (each of which, except for hydrogen, halo, -OH, -O (C ₁ ~C _{4 alkyl), - CN, C 1 ~C} 4 _{alkyl, -NH 2, -NH (C 1} ~C 4 _{alkyl), - N (C 1 ~C} 4 alkyl) ( C ₁ -C ₄ alkyl), - C (O) NH 2, -C (O) NH (C 1 ~C 4 alkyl), - C (O) N (C 1 ~C 4 alkyl) (C ₁ -C ₄ alkyl), - C (O) ( C 1 ~C 4 alkyl), - NHC (O) ( C 1 ~C 4 _{alkyl), - N (C 1 ~C} 4 _{alkyl) C (O) (C 1} ~ C _{4 alkyl), - S (O) n} NH 2, -S (O) n NH (C 1 ~C 4 _{alkyl), - S (O) n} n (C 1 ~C 4 alkyl) (C ₁ -C ₄ alkyl), -S (O) _n (C ₁ -C ₄ alkyl), -NHS (O) _n (C ₁ -C ₄ alkyl), -N (C ₁ -C ₄ alkyl) S (O) _n ( C ₁ -C ₄ alkyl), optionally C ₃ -C ₈ cycloalkyl are substituted, and heterocyclic (C ₁ -C ₄ alkyl 3-8 membered optionally substituted is Optionally substituted by one or more groups selected from: optionally substituted by, halo, -OH, -OMe, -CN, or
Or R ⁵ and R ⁶ , R ⁵ and R ⁷ , R ⁵ and R ⁸ , R ⁵ and R ⁹ , and R ⁵ and R ¹⁰ together with the atoms to which they are attached form a ring It can be, the ring, _{halo, -OH, -O (C 1 ~C} 4 _{alkyl), - CN, C 1 ~C} 4 _{alkyl, -NH 2, -NH (C 1} ~C 4 alkyl), - N (C ₁ -C ₄ alkyl) (C ₁ ~C ₄ alkyl), - C (O) NH 2, -C (O) NH (C 1 ~C 4 alkyl), - C (O) N (C 1 ~ C ₄ alkyl) (C ₁ ~C ₄ alkyl), - C (O) ( C 1 ~C 4 alkyl), - NHC (O) ( C 1 ~C 4 _{alkyl), - N (C 1 ~C} 4 alkyl _{) C (O) (C 1} ~C 4 _{alkyl), - S (O) n} NH 2, -S (O) n NH (C 1 ~C 4 _{alkyl), - S (O) n} n (C 1 ~ C ₄ alkyl) (C ₁ ~C _{4 alkyl), - S (O) n} (C 1 ~C 4 _{alkyl), - NHS (O) n} (C 1 ~C 4 alkyl), - n (C ₁ ~C ₄ alkyl) S (O) _n (C ₁ -C ₄ alkyl), optionally substituted C ₃ -C ₈ cycloalkyl, and optionally substituted 3-8 membered heterocycle (C ₁ -C ₄ alkyl is halo, -OH Optionally substituted by one or more groups selected from: optionally substituted by-, --OMe, or --CN;
L _x is a bond or optionally substituted C ₁ -C ₆ alkylene;
Each of the above optionally substituted groups, where no substituent is specifically specified, can be unsubstituted or, for example, C ₁ -C ₄ alkyl, cycloalkyl, aryl, heterocycle , heteroaryl, aryl -C ₁ -C ₄ alkyl -, heteroaryl -C ₁ -C ₄ alkyl -, C ₁ -C ₄ haloalkyl -, - OC ₁ -C ₄ alkyl, -OC ₁ -C ₄ alkylphenyl, -C ₁ -C ₄ alkyl -OH, -C ₁ -C ₄ alkyl -OC ₁ -C ₄ alkyl, -OC ₁ -C ₄ haloalkyl, _{halo, -OH, -NH 2, -C 1} ~C 4 alkyl - _{NH 2, -N (C 1 ~C} 4 alkyl) (C ₁ ~C _{4 alkyl), - NH (C 1 ~C} 4 _{alkyl), - N (C 1 ~C} 4 alkyl) (C ₁ ~C ₄ alkyl _{phenyl), - NH (C 1 ~C} 4 alkyl phenyl), cyano, nitro, _{oxo, -CO 2 H, -C (O} ) OC 1 ~C 4 alkyl, -CON (C ₁ ~C ₄ alkyl) (C ₁ -C _{4 alkyl), - CONH (C 1 ~C} 4 _{alkyl), - CONH 2, -NHC (} O) ( C ₁ -C ₄ alkyl), - NHC (O) _{(phenyl), - N (C 1 ~C} 4 _{alkyl) C (O) (C 1} ~C 4 _{alkyl), - N (C 1 ~C} 4 alkyl) C (O) (phenyl), - C (O) C 1 ~C 4 _{alkyl, -C (O) (C 3} ~C 8 cycloalkyl), - C (O) ( C 5 ~C 10 aryl), - _{C (O) (C 3 ~C} 8 heterocycle), - C (O) ( C 5 ~C 10 heteroaryl), - C (O) ( C 1 ~C 4 alkyl) - (C ₃ ~C ₈ cycloalkyl alkyl), - C (O) ( C 1 ~C 4 alkyl) - (C ₅ ~C ₁₀ aryl), - C (O) ( C 1 ~C 4 alkyl) - (C ₃ ~C ₈ heterocycle), _{-C (O) (C 1 ~C} 4 alkyl) - (C ₅ ~C ₁₀ heteroaryl), - C (O) C 1 ~C 4 _{haloalkyl, -OC (O) C 1 ~C} 4 alkyl, -SO ₂ (C _{1 ~C 4 alkyl), - SO 2 (C 3} ~C 8 _{cycloalkyl), - SO 2 (C 5} ~C 10 _{aryl), - SO 2 (C 3} ~C 8 heterocycle), - SO ₂ (C _{5 ~C 10 heteroaryl), - SO 2 (C 1} ~C 4 alkyl) - (C ₃ ~C _{8 cycloalkyl), - SO 2 (C 1} ~C 4 alkyl) - (C ₅ ~C _{10 aryl), - SO 2 (C 1} ~C 4 alkyl) - (C ₃ ~C ₈ heterocycle _{), - SO 2 (C 1} ~C 4 alkyl) - (C ₅ ~C _{10 heteroaryl), - SO 2 (C 1} ~C 4 _{haloalkyl), - SO 2 NH 2,} -SO 2 NH (C 1 ~ C _{4 alkyl), - SO 2 N (C} 1 ~C 4 alkyl) (C ₁ -C ₄ alkyl), - SO ₂ NH _{(phenyl), - SO 2 N (C} 1 ~C 4 alkyl) (phenyl), -NHSO ₂ (C ₁ -C ₄ alkyl), - NHSO ₂ (phenyl), and -NHSO ₂ (C ₁ -C ₄ haloalkyl) are independently selected from one or more (one, two or three can be substituted independently by substituent Tsunado), alkyl, cycloalkyl, aryl, heterocycle, and each of the heteroaryl, halo, cycloalkyl, heterocycle, C ₁ -C ₄ alkyl, C ₁ -C ₄ haloalkyl -, - OC _{1 ~C 4} alkyl, C ₁ -C ₄ alkyl -OH, -C ₁ -C ₄ alkyl -OC ₁ -C ₄ alkyl, -OC ₁ -C ₄ haloalkyl, cyano, _{nitro, -NH 2, -OH, -CO 2} H, -C (O) OC 1 ~C 4 alkyl, -CON (C ₁ ~C ₄ alkyl) (C ₁ -C _{4 alkyl), - CONH (C 1 ~C} 4 _{alkyl), - CONH 2, -NHC (} O) (C 1 ~C 4 _{alkyl), - N (C 1 ~C} 4 alkyl) C (O) (C ₁ -C _{4 alkyl), - SO 2 (C 1} ~C 4 alkyl), - SO _{2 (phenyl), - SO 2 (C 1} ~C 4 _{haloalkyl), - SO 2 NH 2,} -SO 2 NH (C ₁ -C _{4 alkyl), - SO 2 N (C} 1 ~C 4 alkyl) (C ₁ -C ₄ alkyl), - SO ₂ NH _{(phenyl), - SO 2 N (C} 1 ~C 4 alkyl) (Phenyl), -NHSO ₂ (C ₁ -C ₄ alkyl), -N (C ₁ -C ₄ alkyl) SO ₂ (C ₁ -C ₄ alkyl), -NHSO ₂ (phenyl), -N (C ₁ -C C ₄ alkyl) SO _{2 (phenyl), - NHSO 2 (C 1} ~C 4 haloalkyl), and -N (C ₁ -C ₄ alkyl) SO ₂ (C ₁ ~C ₄ haloalkyl) one or more selected from Optionally substituted by a group of
m is 0, 1 or 2,
n is 1 or 2,
p is 1, 2 or 3]
Is provided.

  The compounds described herein are useful as inhibitors of SYK. The compounds of the present invention have also been found to show good kinase selectivity for SYK over other kinases such as VEGFR-2 (KDR) or Flt-3.

  Also disclosed are pharmaceutical compositions comprising at least one compound described herein and / or at least one pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier.

  A method of inhibiting the activity of Syk kinase comprising inhibiting said activity with an effective amount of at least one compound described herein and / or at least one pharmaceutically acceptable salt thereof. A method is also provided.

  A method of treating a subject having an inflammatory disease that is recognized to be responsive to inhibition of Syk, in an amount effective to treat said disease, at least one of those described herein Also provided is a method comprising administering a compound and / or at least one pharmaceutically acceptable salt thereof to said subject whose need is recognized.

  As used herein, the following words, phrases, and symbols are generally intended to have the meanings set forth below, except where otherwise indicated by the context in which they are used. The The following abbreviations and terms have the indicated meaning throughout:

A dash ("-") that is not between two letters or symbols is used to indicate a point of attachment for a substituent. For example, —CONH ₂ is bonded through the carbon atom.

  The term “alkyl” as used herein refers to a straight or branched hydrocarbon containing 1 to 18, preferably 1 to 12, more preferably 1 to 6 carbon atoms. Examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl and t-butyl. “Lower alkyl” refers to a straight or branched hydrocarbon containing 1 to 6, preferably 1 to 4 carbon atoms.

  `` Alkoxy '' means, for example, methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, pentoxy, 2-pentyloxy, isopentoxy, neopentoxy, hexoxy, 2-hexoxy, 3-hexoxy, 3 Means a linear or branched alkyl group containing 1 to 18, preferably 1 to 12, more preferably 1 to 6 carbon atoms bonded through an oxygen bond, such as methylpentoxy . An alkoxy group will usually have 1 to 6 carbon atoms attached through an oxygen bond. “Lower alkoxy” refers to straight or branched alkoxy wherein the alkyl moiety contains 1 to 6, preferably 1 to 4 carbon atoms.

  The term “alkenyl” refers herein to a straight or branched hydrocarbon containing one or more C═C double bonds, and 2 to 10, preferably 2 to 6 carbon atoms. Point to. Examples of alkenyl groups include, but are not limited to, vinyl, 2-propenyl and 2-butenyl.

  The term “alkynyl” as used herein refers to a straight or branched hydrocarbon containing one or more C≡C triple bonds and 2 to 10, preferably 2 to 6 carbon atoms. Examples of alkynyl groups include, but are not limited to, ethynyl, 2-propynyl and 2-butynyl.

  The term “alkylene” as used herein refers to branched and unbranched alkylene groups having 1 to 6 carbon atoms. Alkylene groups having 1 to 4 carbon atoms are preferred. Examples of these include, but are not limited to, methylene, ethylene, propylene, 1-methylethylene, butylene, 1-methylpropylene, 1,1-dimethylethylene, 1,2-dimethylethylene, pentylene, 1,1- Dimethylpropylene, 2,2-dimethylpropylene, 1,2-dimethylpropylene, 1,3-dimethylpropylene or hexylene are included. Unless otherwise stated, the definitions propylene, butylene, pentylene and hexylene include all possible isomers of the group of interest having the same number of carbons. Thus, for example, propylene includes 1-methylethylene and butylene includes 1-methylpropylene, 1,1-dimethylethylene, 1,2-dimethylethylene.

  The term “cycloalkyl” refers to saturated and partially unsaturated cyclic hydrocarbon groups having from 3 to 12, preferably from 3 to 8, carbon atoms. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl and cyclooctyl. The ring may be saturated or may have one or more double bonds (ie, partially unsaturated), but is not fully conjugated and is defined herein Not aryl.

“Aryl” means
5- and 6-membered carbocyclic aromatic rings such as benzene,
8- and 12-membered bicyclic ring systems in which at least one ring is carbocyclic and aromatic, such as naphthalene, indane, indoline, indoline-2-one, 2,3-dihydrobenzofuran, benzo [d] [1,3] dioxole and 1,2,3,4-tetrahydroquinoline, chroman, 2,3-dihydrobenzo [b] [1,4] dioxin, 3,4-dihydro-2H-benzo [b] [ 1,4] oxazine, isochroman, 1,3-dihydroisobenzofuran, 1H-benzo [d] [1,3] oxazin-2 (4H) -one, and at least one ring is carbocyclic and aromatic Includes 11- and 14-membered tricyclic ring systems such as fluorene.

  For example, aryl includes 5- and 6-membered carbocyclic aromatic rings fused to a 5- to 7-membered heterocyclic ring containing one or more heteroatoms selected from N, O and S Provided that the point of attachment is on the carbocyclic aromatic ring. A divalent group formed from a substituted benzene derivative and having a free valence on a ring atom is termed a substituted phenylene group. By removing one hydrogen atom from a carbon atom having a free valence, a divalent group derived from a monovalent polycyclic hydrocarbon group whose name ends with `` -yl '' has the corresponding monovalent For example, a naphthyl group having two points of attachment is named naphthylidene. However, aryl never includes or overlaps with heteroaryl, as individually defined below. Thus, when one or more carbocyclic aromatic rings are fused with a heteroaromatic ring, the resulting ring system is heteroaryl and not aryl as defined herein .

  The term “halo” includes fluoro, chloro, bromo and iodo, and the term “halogen” includes fluorine, chlorine, bromine and iodine.

The term “heteroaryl”
1-8 or more selected from N, O and S, such as 1-4, or in some embodiments, 1-3, containing 1-3 heteroatoms and the remaining ring atoms are carbon, 5-8 A member of an aromatic monocyclic ring,
One or more selected from N, O and S, for example 1 to 4, or in some embodiments, 1 to 3 heteroatoms, the remaining ring atoms are carbon, and at least 1 An 8- to 12-membered bicyclic ring in which heteroatoms are present in the aromatic ring, and
One or more selected from N, O and S, for example 1 to 4, or in some embodiments, 1 to 3 heteroatoms, the remaining ring atoms are carbon, and at least 1 Refers to an 11-14 membered tricyclic ring in which the heteroatoms are present in an aromatic ring.

  For example, heteroaryl includes a 5-7 membered heteroaromatic ring fused to a 5-7 membered cycloalkyl ring. In such fused bicyclic heteroaryl ring systems where only one of the rings contains one or more heteroatoms, the point of attachment is on the heteroaromatic ring.

  When the total number of S and O atoms in a heteroaryl group exceeds 1, those heteroatoms are not adjacent to one another. In some embodiments, the total number of S and O atoms in the heteroaryl group is 2 or less. In some embodiments, the total number of S and O atoms in the aromatic heterocycle is 1 or less.

  Examples of heteroaryl groups include, but are not limited to, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2,3-pyrazinyl, 3 (when numbering from the linking position assigned priority 1) , 4-pyrazinyl, 2,4-pyrimidinyl, 3,5-pyrimidinyl, 1-pyrazolyl, 2,3-pyrazolyl, 2,4-imidazolinyl, isoxazolyl, oxazolyl, thiazolyl, thiadiazolyl, tetrazolyl, thienyl, benzothienyl, furyl, Benzofuryl, benzimidazolinyl, indolinyl, pyrididinyl, triazolyl, quinolinyl, pyrazolyl, and 5,6,7,8-tetrahydroisoquinoline are included.

  A divalent group derived from a monovalent heteroaryl group whose name ends with "-yl" by removing one hydrogen atom from the atom having the free valence is the name of the corresponding monovalent group For example, a pyridyl group having two points of attachment is named pyridylidene. Heteroaryl does not include or overlap with aryl as defined above.

Substituted heteroaryl also includes ring systems substituted with one or more oxide (—O ⁻ ) substituents, such as pyridinyl N-oxide.

  `` Heterocycle '' means 3 to 12 members (preferably 3 to 8) containing at least 2 carbon atoms in addition to 1 to 3 heteroatoms independently selected from oxygen, sulfur and nitrogen Member) monocyclic, bicyclic or tricyclic saturated or partially unsaturated rings. “Heterocycle” is selected from N, O and S fused to a 5-, 6- and / or 7-membered cycloalkyl, heterocyclic, carbocyclic aromatic or heteroaromatic ring Also refers to 5- to 7-membered heterocyclic rings containing one or more heteroatoms, provided that the point of attachment is in the heterocyclic ring. “Heterocycle” also refers to an aliphatic spirocyclic ring containing one or more heteroatoms selected from N, O and S, provided that the point of attachment is in the heterocyclic ring. The ring may be saturated or may have one or more double bonds (ie partially unsaturated). Heterocycles can be substituted by oxo. The point of attachment may be a carbon or heteroatom within the heterocyclic ring. A heterocycle is not a heteroaryl as defined herein.

  Suitable heterocycles include, for example (when numbering from the linking position assigned priority 1), 1-pyrrolidinyl, 2-pyrrolidinyl, 2,4-imidazolidinyl, 2,3-pyrazolidinyl, 1-piperidinyl, 2 -Piperidinyl, 3-piperidinyl, 4-piperidinyl, and 2,5-piperazinyl are included. Morpholinyl groups are also contemplated, including 2-morpholinyl and 3-morpholinyl (numbered when oxygen is assigned priority 1). A substituted heterocycle is substituted by one or more oxo moieties such as piperidinyl N-oxide, morpholinyl-N-oxide, 1-oxo-1-thiomorpholinyl, and 1,1-dioxo-1-thiomorpholinyl. Also included are ring systems.

  “Any” or “optional” means that the event or situation described thereafter may or may not occur, and that the description includes examples of the event or situation occurring, and It means that examples where it doesn't happen are included. For example, “optionally substituted alkyl” includes both “unsubstituted alkyl” and “substituted alkyl” as defined below. With respect to any group containing one or more substituents, such groups may be any substitution that is sterically impractical, synthetically infeasible, and / or inherently unstable. It will also be appreciated by those skilled in the art that it is not intended to introduce substitution patterns.

  The term “substituted” as used herein means that either a designated atom or one or more hydrogens on a group is replaced by one selected from the groups displayed. However, provided that the normal valence of the designated atom is not exceeded. When the substituent is oxo (ie, ═O), two hydrogens on the atom are replaced. Combinations of substituents and / or variables are acceptable only if such combinations result in stable compounds or useful synthetic intermediates. By stable compound or stable structure is meant to imply a compound that does not degrade upon isolation from the reaction mixture and that is at least robust enough for subsequent formulation as a drug with practical convenience. Unless otherwise specified, substituents are named within the core structure. For example, if (cycloalkyl) alkyl is listed as a possible substituent, it should be understood that the point of attachment of the substituent to the core structure is in the alkyl moiety.

  In some embodiments, “substituted by one or more groups” means that the two hydrogens on the specified atom or group are by two selected from the indicated group of substituents. It means being replaced independently. In some embodiments, “substituted by one or more groups” means that three hydrogens on the specified atom or group are selected from the three listed groups of substituents. It means being replaced independently. In some embodiments, “substituted by one or more groups” means that the four hydrogens on the specified atom or group are by four selected from the indicated group of substituents. It means being replaced independently.

  The compounds described herein include, but are not limited to, their regioisomers, their N-, to the extent that they can be made by those skilled in the art without undue experimentation, if possible. Oxide derivatives, their optical isomers, such as enantiomers and diastereomers, mixtures of enantiomers, including racemates, mixtures of diastereomers, and they can be made by one skilled in the art by routine experimentation. To the extent possible these other mixtures are included. In such situations, single enantiomers or diastereomers, i.e. optically active forms, can be obtained by asymmetric synthesis or by resolution of racemates or enantiomeric or diastereomeric mixtures. Resolution of racemates, or diastereomeric mixtures, if possible, by conventional methods such as crystallization in the presence of a resolving agent or chromatography using, for example, chiral high performance liquid chromatography (HPLC) columns. Can be achieved. Further, where possible, such compounds include Z and E forms (or cis and trans forms) of compounds having a carbon-carbon double bond. Where the compounds described herein exist in various tautomeric forms, the term “compound” refers to all tautomeric forms of the compounds to the extent that they can be made without undue experimentation. It is intended to include variants. Such compounds also include crystalline forms, including polymorphs and inclusion compounds, to the extent that they can be made by one skilled in the art without undue experimentation. Similarly, the term “salt” includes all isomers, racemates, other mixtures, Z and E forms, tautomers and crystal forms of a salt of a compound without undue experimentation. It is intended to be included to the extent that it can be made by a vendor.

“Pharmaceutically acceptable salts” include, but are not limited to, hydrochloride, phosphate, diphosphate, hydrobromide, sulfate, sulfinate, nitrate, and similar salts Salts with inorganic acids, as well as malate, maleate, fumarate, tartrate, succinate, citrate, acetate, lactate, methanesulfonate, p-toluenesulfonate, 2- Hydroxyethyl sulfonate, benzoate, salicylate, stearate, and salts with organic acids such as alkaneates such as acetate, HOOC- (CH ₂ ) _n —COOH where n is 0-4 And similar salts. Similarly, pharmaceutically acceptable cations include, but are not limited to sodium, potassium, calcium, aluminum, lithium and ammonium.

  Furthermore, when the compounds described herein are obtained as acid addition salts, the free base can be obtained by basifying a solution of the acid salt. Conversely, when the product is a free base, the addition salt, particularly a pharmaceutically acceptable addition salt, is dissolved in a suitable organic solvent according to conventional procedures for preparing acid addition salts from basic compounds. It can be produced by dissolving the free base and treating this solution with acid. Those skilled in the art will recognize various synthetic methods that can be used without undue experimentation to prepare non-toxic pharmaceutically acceptable addition salts.

  “Solvates” such as “hydrates” are formed by the interaction of a solvent and a compound. The term “compound” is intended to include solvates, including hydrates of compounds, to the extent that they can be made by one of ordinary skill in the art through routine experimentation. Similarly, “salts” include solvates, such as hydrates of salts, to the extent that they can be made by one of ordinary skill in the art through routine experimentation. Suitable solvates are pharmaceutically acceptable solvents to the extent that they can be made by one skilled in the art by routine experimentation, such as hydrates including monohydrates and hemihydrates. It is a Japanese product.

  As used herein, the terms “group”, “radical”, or “fragment” are synonymous and are a molecular functional group or fragment capable of binding to a molecular bond or other fragment. Is intended to indicate.

  The term “active agent” is used to indicate a chemical having biological activity. In some embodiments, an “active agent” is a chemical having pharmaceutical utility.

  “Treating”, “treat” or “treatment” or “reduction” refers to at least one compound and / or at least one pharmaceutically acceptable agent described herein. To a subject having a disease or disorder, or having a symptom of a disease or disorder, or a predisposition towards a disease or disorder, or a symptom of cancer, disease or disorder, or a disease or disorder It refers to administration for the purpose of curing, curing, reducing, alleviating, changing, treating, ameliorating, ameliorating, or affecting a predisposition. In some embodiments, the disease or disorder can be cancer. In some embodiments, the disease or disorder can be an inflammatory disease.

  The term “effective amount” refers to at least one compound described herein that is effective in “treating” a disease or disorder in a subject responsive to inhibition of Syk, as defined above. And / or refers to the amount of at least one pharmaceutically acceptable salt thereof. An effective amount can cause either an observable or measurable change in a subject, as described in the definitions of “treating”, “treating”, “treatment”, and “reduction” above. it can. For example, in the case of cancer, an effective amount is tumor cells to peripheral organs, including reducing the number of cancer or tumor cells, reducing tumor size, eg spreading of the tumor to soft tissue and bone Inhibit or stop invasion of cancer, inhibit and stop tumor metastasis, inhibit and stop tumor growth, alleviate one or more symptoms associated with cancer to some extent, morbidity rate and It can reduce mortality, improve quality of life, or a combination of these effects. An effective amount can be an amount sufficient to reduce the symptoms of the disease in response to inhibition of Syk kinase.

  The term “effective amount” refers to at least one compound described herein and / or at least one pharmaceutically acceptable that is effective to inhibit the activity of Syk in a subject responsive to inhibition of Syk. The amount of salt made can also refer to.

  The term “inhibit” refers to a decrease in the baseline activity of a biological activity or process. “Inhibition of Syk” refers to at least one compound described herein as compared to the activity of Syk kinase in the absence of at least one compound and / or at least one pharmaceutically acceptable salt thereof. And / or refers to a decrease in the activity of Syk kinase as it responds directly or indirectly to the presence of at least one pharmaceutically acceptable salt thereof. The reduction in activity is due to a direct interaction of at least one compound described herein and / or at least one pharmaceutically acceptable salt thereof with Syk kinase, or described herein. The interaction of at least one compound and / or at least one pharmaceutically acceptable salt thereof with one or more other factors affecting the activity of at least one kinase. it can. For example, the presence of at least one compound described herein and / or at least one pharmaceutically acceptable salt thereof reduces at least one kinase activity by binding directly to Syk kinase. Reduce at least one kinase activity by causing another factor (directly or indirectly) or by reducing (directly or indirectly) the amount of at least one kinase present in the cell or organism. Can do.

DETAILED DESCRIPTION OF THE INVENTION At least one compound of formula (I)

及び/又はそのラセミ混合物、鏡像異性体、ジアステレオマー、互変異性体、若しくは任意の比の混合物、或いは少なくとも1つの薬学的に許容されるそれらの塩若しくは溶媒和物
[式中、
R¹は、水素、ハロ、-CN、-OH、場合により置換されているC₁〜C₆アルキル、場合により置換されているC₁〜C₆アルコキシ、-NH₂、-NH(C₁〜C₄アルキル)、及び-N(C₁〜C₄アルキル)(C₁〜C₄アルキル)から独立して選択され、
R²は、アリール又はヘテロアリール(これらの各々は、ハロ、-NR⁵R⁶、-OR⁷、-S(O)_nR⁸、-C(O)R⁹、-C(O)OR⁷、-CN、-C(O)NR⁵R⁶、-NR⁵C(O)R⁹、-NR⁵S(O)_nR⁸、-NR⁵S(O)_nNR¹⁰R¹¹、-NR⁵C(O)OR⁷、-NR⁵C(O)NR¹⁰R¹¹、-NO₂、-S(O)_nNR⁵R⁶、場合により置換されている低級アルキル、場合により置換されているシクロアルキル、場合により置換されている複素環、場合により置換されているヘテロアリール、場合により置換されているアリール、場合により置換されているアルケニル、及び場合により置換されているアルキニルから選択される1つ以上の基により場合により置換されている)であり、
Lは、結合又は場合により置換されているC₁〜C₆アルキレンであり、
Wは、シクロアルキル、複素環、アリール、又はヘテロアリールであり、
R³は、水素、-Lx-ハロ、-Lx-R⁴、-Lx-NR⁵R⁶、-Lx-OR⁷、-Lx-S(O)_nR⁸、-Lx-C(O)R⁹、-S(O)_n-Lx-R⁸、-C(O)-Lx-R⁹、-Lx-CN、-Lx-NR⁵C(O)R⁹、-Lx-NR⁵S(O)_nR⁸、-Lx-NR⁵C(O)NR¹⁰R¹¹、-Lx-NR⁵S(O)_nNR¹⁰R¹¹、-Lx-NR⁵C(O)OR⁷、-Lx-NR⁵S(O)_nOR⁷、-NO₂、-Lx-C(O)NR⁵R⁶、-Lx-S(O)_nNR⁵R⁶、オキソ(=O)、場合により置換されているシクロアルキル、場合により置換されている複素環、場合により置換されているヘテロアリール、及び場合により置換されているアリールから独立して選択されるが、
ただし、Lがメチレンであり、且つWが5員又は6員の複素環である場合、R³は、-Lx-NR⁵R⁶、-Lx-OR⁷、-Lx-S(O)_nR⁸、-Lx-C(O)R⁹、-S(O)_n-Lx-R⁸、-C(O)-Lx-R⁹、-Lx-CN、-Lx-NR⁵C(O)R⁹、-Lx-NR⁵S(O)_nR⁸、-Lx-NR⁵C(O)NR¹⁰R¹¹、-Lx-NR⁵S(O)_nNR¹⁰R¹¹、-Lx-NR⁵C(O)OR⁷、-Lx-NR⁵S(O)_nOR⁷、-NO₂、-Lx-C(O)NR⁵R⁶、-Lx-S(O)_nNR⁵R⁶、オキソ(=O)、場合により置換されているシクロアルキル、場合により置換されている複素環、場合により置換されているヘテロアリール、及び場合により置換されているアリールから独立して選択されることを条件とし、
R⁴は、C₁〜C₆アルキル、C₂〜C₆アルケニル、又はC₂〜C₆アルキニル(これらの各々は、場合により置換されている)であり、
R⁵、R⁶、R⁷、R⁸、R⁹、R¹⁰及びR¹¹は、水素、アルキル、シクロアルキル、アリール、ヘテロアリール、及び複素環(これらの各々は、水素を除いて、ハロ、-OH、-O(C₁〜C₄アルキル)、-CN、C₁〜C₄アルキル、-NH₂、-NH(C₁〜C₄アルキル)、-N(C₁〜C₄アルキル)(C₁〜C₄アルキル)、-C(O)NH₂、-C(O)NH(C₁〜C₄アルキル)、-C(O)N(C₁〜C₄アルキル)(C₁〜C₄アルキル)、-C(O)(C₁〜C₄アルキル)、-NHC(O)(C₁〜C₄アルキル)、-N(C₁〜C₄アルキル)C(O)(C₁〜C₄アルキル)、-S(O)_nNH₂、-S(O)_nNH(C₁〜C₄アルキル)、-S(O)_nN(C₁〜C₄アルキル)(C₁〜C₄アルキル)、-S(O)_n(C₁〜C₄アルキル)、-NHS(O)_n(C₁〜C₄アルキル)、-N(C₁〜C₄アルキル)S(O)_n(C₁〜C₄アルキル)、場合により置換されているC₃〜C₈シクロアルキル、及び場合により置換されている3〜8員の複素環(C₁〜C₄アルキルは、ハロ、-OH、-OMe、-CNにより場合により置換されている)から選択される1つ以上の基により場合により置換されている)から独立して選択されるか、
又はR⁵とR⁶、R⁵とR⁷、R⁵とR⁸、R⁵とR⁹、及びR⁵とR¹⁰は、それらが結合している原子と一緒になって環を形成することができ、この環は、ハロ、-OH、-O(C₁〜C₄アルキル)、-CN、C₁〜C₄アルキル、-NH₂、-NH(C₁〜C₄アルキル)、-N(C₁〜C₄アルキル)(C₁〜C₄アルキル)、-C(O)NH₂、-C(O)NH(C₁〜C₄アルキル)、-C(O)N(C₁〜C₄アルキル)(C₁〜C₄アルキル)、-C(O)(C₁〜C₄アルキル)、-NHC(O)(C₁〜C₄アルキル)、-N(C₁〜C₄アルキル)C(O)(C₁〜C₄アルキル)、-S(O)_nNH₂、-S(O)_nNH(C₁〜C₄アルキル)、-S(O)_nN(C₁〜C₄アルキル)(C₁〜C₄アルキル)、-S(O)_n(C₁〜C₄アルキル)、-NHS(O)_n(C₁〜C₄アルキル)、-N(C₁〜C₄アルキル)S(O)_n(C₁〜C₄アルキル)、場合により置換されているC₃〜C₈シクロアルキル、及び場合により置換されている3〜8員の複素環(C₁〜C₄アルキルは、ハロ、-OH、-OMe、又は-CNにより場合により置換されている)から選択される1つ以上の基により場合により置換されており、
L_xは、結合又は場合により置換されているC₁〜C₆アルキレンであり、
置換基が具体的に指定されていない、上記の場合により置換されている基の各々は、無置換とすることができるか、又は例えば、C₁〜C₄アルキル、シクロアルキル、アリール、複素環、ヘテロアリール、アリール-C₁〜C₄アルキル-、ヘテロアリール-C₁〜C₄アルキル-、C₁〜C₄ハロアルキル-、-OC₁〜C₄アルキル、-OC₁〜C₄アルキルフェニル、-C₁〜C₄アルキル-OH、-C₁〜C₄アルキル-O-C₁〜C₄アルキル、-OC₁〜C₄ハロアルキル、ハロ、-OH、-NH₂、-C₁〜C₄アルキル-NH₂、-N(C₁〜C₄アルキル)(C₁〜C₄アルキル)、-NH(C₁〜C₄アルキル)、-N(C₁〜C₄アルキル)(C₁〜C₄アルキルフェニル)、-NH(C₁〜C₄アルキルフェニル)、シアノ、ニトロ、オキソ、-CO₂H、-C(O)OC₁〜C₄アルキル、-CON(C₁〜C₄アルキル)(C₁〜C₄アルキル)、-CONH(C₁〜C₄アルキル)、-CONH₂、-NHC(O)(C₁〜C₄アルキル)、-NHC(O)(フェニル)、-N(C₁〜C₄アルキル)C(O)(C₁〜C₄アルキル)、-N(C₁〜C₄アルキル)C(O)(フェニル)、-C(O)C₁〜C₄アルキル、-C(O)(C₃〜C₈シクロアルキル)、-C(O)(C₅〜C₁₀アリール)、-C(O)(C₃〜C₈複素環)、-C(O)(C₅〜C₁₀ヘテロアリール)、-C(O)(C₁〜C₄アルキル)-(C₃〜C₈シクロアルキル)、-C(O)(C₁〜C₄アルキル)-(C₅〜C₁₀アリール)、-C(O)(C₁〜C₄アルキル)-(C₃〜C₈複素環)、-C(O)(C₁〜C₄アルキル)-(C₅〜C₁₀ヘテロアリール)、-C(O)C₁〜C₄ハロアルキル、-OC(O)C₁〜C₄アルキル、-SO₂(C₁〜C₄アルキル)、-SO₂(C₃〜C₈シクロアルキル)、-SO₂(C₅〜C₁₀アリール)、-SO₂(C₃〜C₈複素環)、-SO₂(C₅〜C₁₀ヘテロアリール)、-SO₂(C₁〜C₄アルキル)-(C₃〜C₈シクロアルキル)、-SO₂(C₁〜C₄アルキル)-(C₅〜C₁₀アリール)、-SO₂(C₁〜C₄アルキル)-(C₃〜C₈複素環)、-SO₂(C₁〜C₄アルキル)-(C₅〜C₁₀ヘテロアリール)、-SO₂(C₁〜C₄ハロアルキル)、-SO₂NH₂、-SO₂NH(C₁〜C₄アルキル)、-SO₂N(C₁〜C₄アルキル)(C₁〜C₄アルキル)、-SO₂NH(フェニル)、-SO₂N(C₁〜C₄アルキル)(フェニル)、-NHSO₂(C₁〜C₄アルキル)、-NHSO₂(フェニル)、及び-NHSO₂(C₁〜C₄ハロアルキル)から独立して選択される、1つ以上(1つ、2つ又は3つなど)の置換基により独立して置換されていることができ、アルキル、シクロアルキル、アリール、複素環、及びヘテロアリールの各々は、ハロ、シクロアルキル、複素環、C₁〜C₄アルキル、C₁〜C₄ハロアルキル-、-OC₁〜C₄アルキル、C₁〜C₄アルキル-OH、-C₁〜C₄アルキル-O-C₁〜C₄アルキル、-OC₁〜C₄ハロアルキル、シアノ、ニトロ、-NH₂、-OH、-CO₂H、-C(O)OC₁〜C₄アルキル、-CON(C₁〜C₄アルキル)(C₁〜C₄アルキル)、-CONH(C₁〜C₄アルキル)、-CONH₂、-NHC(O)(C₁〜C₄アルキル)、-N(C₁〜C₄アルキル)C(O)(C₁〜C₄アルキル)、-SO₂(C₁〜C₄アルキル)、-SO₂(フェニル)、-SO₂(C₁〜C₄ハロアルキル)、-SO₂NH₂、-SO₂NH(C₁〜C₄アルキル)、-SO₂N(C₁〜C₄アルキル)(C₁〜C₄アルキル)、-SO₂NH(フェニル)、-SO₂N(C₁〜C₄アルキル)(フェニル)、-NHSO₂(C₁〜C₄アルキル)、-N(C₁〜C₄アルキル)SO₂(C₁〜C₄アルキル)、-NHSO₂(フェニル)、-N(C₁〜C₄アルキル)SO₂(フェニル)、-NHSO₂(C₁〜C₄ハロアルキル)、及び-N(C₁〜C₄アルキル)SO₂(C₁〜C₄ハロアルキル)から選択される1つ以上の基により場合により置換されており、
mは、0、1又は2であり、
nは、1又は2であり、
pは、1、2又は3である]
が提供される。

And / or racemic mixtures, enantiomers, diastereomers, tautomers, or mixtures in any ratio, or at least one pharmaceutically acceptable salt or solvate thereof
[Where
R ¹ is hydrogen, halo, -CN, -OH, optionally C ₁ -C ₆ alkyl optionally substituted, optionally C ₁ -C ₆ alkoxy _{substituted, -NH 2, -NH (C 1} ~ C ₄ alkyl), and are independently selected from -N (C ₁ ~C ₄ alkyl) (C ₁ -C ₄ alkyl),
R ² is aryl or heteroaryl (each of which is halo, -NR ⁵ R ⁶ , -OR ⁷ , -S (O) _n R ⁸ , -C (O) R ⁹ , -C (O) OR ⁷ , -CN, -C (O) NR ⁵ R ⁶ , -NR ⁵ C (O) R ⁹ , -NR ⁵ S (O) _n R ⁸ , -NR ⁵ S (O) _n NR ¹⁰ R ¹¹ , -NR ⁵ C (O) OR ⁷ , —NR ⁵ C (O) NR ¹⁰ R ¹¹ , —NO ₂ , —S (O) _n NR ⁵ R ⁶ , optionally substituted lower alkyl, optionally substituted 1 selected from cycloalkyl, optionally substituted heterocycle, optionally substituted heteroaryl, optionally substituted aryl, optionally substituted alkenyl, and optionally substituted alkynyl. Optionally substituted by two or more groups),
L is a C ₁ -C ₆ alkylene substituted by binding or case,
W is cycloalkyl, heterocycle, aryl, or heteroaryl;
R ³ is hydrogen, -Lx-halo, -Lx-R ⁴ , -Lx-NR ⁵ R ⁶ , -Lx-OR ⁷ , -Lx-S (O) _n R ⁸ , -Lx-C (O) R ⁹ , -S (O) _n -Lx-R ⁸ , -C (O) -Lx-R ⁹ , -Lx-CN, -Lx-NR ⁵ C (O) R ⁹ , -Lx-NR ⁵ S (O ) _n R ⁸ , -Lx-NR ⁵ C (O) NR ¹⁰ R ¹¹ , -Lx-NR ⁵ S (O) _n NR ¹⁰ R ¹¹ , -Lx-NR ⁵ C (O) OR ⁷ , -Lx-NR ⁵ S (O) _n OR ⁷ , -NO ₂ , -Lx-C (O) NR ⁵ R ⁶ , -Lx-S (O) _n NR ⁵ R ⁶ , oxo (= O), optionally substituted Independently selected from cycloalkyl, optionally substituted heterocycle, optionally substituted heteroaryl, and optionally substituted aryl,
However, when L is methylene and W is a 5- or 6-membered heterocyclic ring, R ³ is -Lx-NR ⁵ R ⁶ , -Lx-OR ⁷ , -Lx-S (O) _n R ⁸ , -Lx-C (O) R ⁹ , -S (O) _n -Lx-R ⁸ , -C (O) -Lx-R ⁹ , -Lx-CN, -Lx-NR ⁵ C (O) R ⁹ , -Lx-NR ⁵ S (O) _n R ⁸ , -Lx-NR ⁵ C (O) NR ¹⁰ R ¹¹ , -Lx-NR ⁵ S (O) _n NR ¹⁰ R ¹¹ , -Lx-NR ⁵ C (O) OR ⁷ , -Lx-NR ⁵ S (O) _n OR ⁷ , -NO ₂ , -Lx-C (O) NR ⁵ R ⁶ , -Lx-S (O) _n NR ⁵ R ⁶ , oxo ( = O), optionally substituted cycloalkyl, optionally substituted heterocycle, optionally substituted heteroaryl, and optionally substituted aryl. ,
R ⁴ is C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, or C ₂ -C ₆ alkynyl, each of which is optionally substituted;
R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ and R ¹¹ are hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, and heterocycle (each of which, except for hydrogen, halo, -OH, -O (C ₁ ~C _{4 alkyl), - CN, C 1 ~C} 4 _{alkyl, -NH 2, -NH (C 1} ~C 4 _{alkyl), - N (C 1 ~C} 4 alkyl) ( C ₁ -C ₄ alkyl), - C (O) NH 2, -C (O) NH (C 1 ~C 4 alkyl), - C (O) N (C 1 ~C 4 alkyl) (C ₁ -C ₄ alkyl), - C (O) ( C 1 ~C 4 alkyl), - NHC (O) ( C 1 ~C 4 _{alkyl), - N (C 1 ~C} 4 _{alkyl) C (O) (C 1} ~ C _{4 alkyl), - S (O) n} NH 2, -S (O) n NH (C 1 ~C 4 _{alkyl), - S (O) n} n (C 1 ~C 4 alkyl) (C ₁ -C ₄ alkyl), -S (O) _n (C ₁ -C ₄ alkyl), -NHS (O) _n (C ₁ -C ₄ alkyl), -N (C ₁ -C ₄ alkyl) S (O) _n ( C ₁ -C ₄ alkyl), optionally C ₃ -C ₈ cycloalkyl are substituted, and heterocyclic (C ₁ -C ₄ alkyl 3-8 membered optionally substituted is Optionally substituted by one or more groups selected from: optionally substituted by, halo, -OH, -OMe, -CN, or
Or R ⁵ and R ⁶ , R ⁵ and R ⁷ , R ⁵ and R ⁸ , R ⁵ and R ⁹ , and R ⁵ and R ¹⁰ together with the atoms to which they are attached form a ring It can be, the ring, _{halo, -OH, -O (C 1 ~C} 4 _{alkyl), - CN, C 1 ~C} 4 _{alkyl, -NH 2, -NH (C 1} ~C 4 alkyl), - N (C ₁ -C ₄ alkyl) (C ₁ ~C ₄ alkyl), - C (O) NH 2, -C (O) NH (C 1 ~C 4 alkyl), - C (O) N (C 1 ~ C ₄ alkyl) (C ₁ ~C ₄ alkyl), - C (O) ( C 1 ~C 4 alkyl), - NHC (O) ( C 1 ~C 4 _{alkyl), - N (C 1 ~C} 4 alkyl _{) C (O) (C 1} ~C 4 _{alkyl), - S (O) n} NH 2, -S (O) n NH (C 1 ~C 4 _{alkyl), - S (O) n} n (C 1 ~ C ₄ alkyl) (C ₁ ~C _{4 alkyl), - S (O) n} (C 1 ~C 4 _{alkyl), - NHS (O) n} (C 1 ~C 4 alkyl), - n (C ₁ ~C ₄ alkyl) S (O) _n (C ₁ -C ₄ alkyl), optionally substituted C ₃ -C ₈ cycloalkyl, and optionally substituted 3-8 membered heterocycle (C ₁ -C ₄ alkyl is halo, -OH Optionally substituted by one or more groups selected from: optionally substituted by-, --OMe, or --CN;
L _x is a bond or optionally substituted C ₁ -C ₆ alkylene;
Each of the above optionally substituted groups, where no substituent is specifically specified, can be unsubstituted or, for example, C ₁ -C ₄ alkyl, cycloalkyl, aryl, heterocycle , heteroaryl, aryl -C ₁ -C ₄ alkyl -, heteroaryl -C ₁ -C ₄ alkyl -, C ₁ -C ₄ haloalkyl -, - OC ₁ -C ₄ alkyl, -OC ₁ -C ₄ alkylphenyl, -C ₁ -C ₄ alkyl -OH, -C ₁ -C ₄ alkyl -OC ₁ -C ₄ alkyl, -OC ₁ -C ₄ haloalkyl, _{halo, -OH, -NH 2, -C 1} ~C 4 alkyl - _{NH 2, -N (C 1 ~C} 4 alkyl) (C ₁ ~C _{4 alkyl), - NH (C 1 ~C} 4 _{alkyl), - N (C 1 ~C} 4 alkyl) (C ₁ ~C ₄ alkyl _{phenyl), - NH (C 1 ~C} 4 alkyl phenyl), cyano, nitro, _{oxo, -CO 2 H, -C (O} ) OC 1 ~C 4 alkyl, -CON (C ₁ ~C ₄ alkyl) (C ₁ -C _{4 alkyl), - CONH (C 1 ~C} 4 _{alkyl), - CONH 2, -NHC (} O) ( C ₁ -C ₄ alkyl), - NHC (O) _{(phenyl), - N (C 1 ~C} 4 _{alkyl) C (O) (C 1} ~C 4 _{alkyl), - N (C 1 ~C} 4 alkyl) C (O) (phenyl), - C (O) C 1 ~C 4 _{alkyl, -C (O) (C 3} ~C 8 cycloalkyl), - C (O) ( C 5 ~C 10 aryl), - _{C (O) (C 3 ~C} 8 heterocycle), - C (O) ( C 5 ~C 10 heteroaryl), - C (O) ( C 1 ~C 4 alkyl) - (C ₃ ~C ₈ cycloalkyl alkyl), - C (O) ( C 1 ~C 4 alkyl) - (C ₅ ~C ₁₀ aryl), - C (O) ( C 1 ~C 4 alkyl) - (C ₃ ~C ₈ heterocycle), _{-C (O) (C 1 ~C} 4 alkyl) - (C ₅ ~C ₁₀ heteroaryl), - C (O) C 1 ~C 4 _{haloalkyl, -OC (O) C 1 ~C} 4 alkyl, -SO ₂ (C _{1 ~C 4 alkyl), - SO 2 (C 3} ~C 8 _{cycloalkyl), - SO 2 (C 5} ~C 10 _{aryl), - SO 2 (C 3} ~C 8 heterocycle), - SO ₂ (C _{5 ~C 10 heteroaryl), - SO 2 (C 1} ~C 4 alkyl) - (C ₃ ~C _{8 cycloalkyl), - SO 2 (C 1} ~C 4 alkyl) - (C ₅ ~C _{10 aryl), - SO 2 (C 1} ~C 4 alkyl) - (C ₃ ~C ₈ heterocycle _{), - SO 2 (C 1} ~C 4 alkyl) - (C ₅ ~C _{10 heteroaryl), - SO 2 (C 1} ~C 4 _{haloalkyl), - SO 2 NH 2,} -SO 2 NH (C 1 ~ C _{4 alkyl), - SO 2 N (C} 1 ~C 4 alkyl) (C ₁ -C ₄ alkyl), - SO ₂ NH _{(phenyl), - SO 2 N (C} 1 ~C 4 alkyl) (phenyl), -NHSO ₂ (C ₁ -C ₄ alkyl), - NHSO ₂ (phenyl), and -NHSO ₂ (C ₁ -C ₄ haloalkyl) are independently selected from one or more (one, two or three can be substituted independently by substituent Tsunado), alkyl, cycloalkyl, aryl, heterocycle, and each of the heteroaryl, halo, cycloalkyl, heterocycle, C ₁ -C ₄ alkyl, C ₁ -C ₄ haloalkyl -, - OC _{1 ~C 4} alkyl, C ₁ -C ₄ alkyl -OH, -C ₁ -C ₄ alkyl -OC ₁ -C ₄ alkyl, -OC ₁ -C ₄ haloalkyl, cyano, _{nitro, -NH 2, -OH, -CO 2} H, -C (O) OC 1 ~C 4 alkyl, -CON (C ₁ ~C ₄ alkyl) (C ₁ -C _{4 alkyl), - CONH (C 1 ~C} 4 _{alkyl), - CONH 2, -NHC (} O) (C 1 ~C 4 _{alkyl), - N (C 1 ~C} 4 alkyl) C (O) (C ₁ -C _{4 alkyl), - SO 2 (C 1} ~C 4 alkyl), - SO _{2 (phenyl), - SO 2 (C 1} ~C 4 _{haloalkyl), - SO 2 NH 2,} -SO 2 NH (C ₁ -C _{4 alkyl), - SO 2 N (C} 1 ~C 4 alkyl) (C ₁ -C ₄ alkyl), - SO ₂ NH _{(phenyl), - SO 2 N (C} 1 ~C 4 alkyl) (Phenyl), -NHSO ₂ (C ₁ -C ₄ alkyl), -N (C ₁ -C ₄ alkyl) SO ₂ (C ₁ -C ₄ alkyl), -NHSO ₂ (phenyl), -N (C ₁ -C C ₄ alkyl) SO _{2 (phenyl), - NHSO 2 (C 1} ~C 4 haloalkyl), and -N (C ₁ -C ₄ alkyl) SO ₂ (C ₁ ~C ₄ haloalkyl) one or more selected from Optionally substituted by a group of
m is 0, 1 or 2,
n is 1 or 2,
p is 1, 2 or 3]
Is provided.

In some embodiments, R ¹ is hydrogen, halo, —OH, —CN, optionally substituted C ₁ -C ₆ alkyl, and optionally substituted C ₁ -C ₆ alkoxy, —NH ₂ , —NH (C ₁ -C ₄ alkyl), and —N (C ₁ -C ₄ alkyl) (C ₁ -C ₄ alkyl) are independently selected.

In some embodiments, R ¹ is independently selected from hydrogen, halo, —CN, hydroxyl, or methyl, ethyl, n-propyl, i-propyl, —NH ₂ , N-methylamino, N, N-dimethylamino, N-ethylamino, Nn-propylamino, Ni-propylamino, methoxy, ethoxy, propoxy, and isopropoxy, each of which is optionally substituted.

In some embodiments, R ¹ is hydrogen.

  In some embodiments, m is 1.

  In some embodiments, p is 1 or 2.

In some embodiments, R ² is C ₅ -C ₁₀ aryl or 5-10 membered heteroaryl, each of which is halo, —NR ⁵ R ⁶ , —OR ⁷ , —S (O) _n R ⁸ , -C (O) R ⁹ , -C (O) OR ⁷ , -CN, -C (O) NR ⁵ R ⁶ , -NR ⁵ C (O) R ⁹ , -NR ⁵ S (O) _n R ⁸ , -NR ⁵ S (O) _n NR ¹⁰ R ¹¹ , -NR ⁵ C (O) OR ⁷ , -NR ⁵ C (O) NR ¹⁰ R ¹¹ , -NO ₂ , -S (O) _n NR ⁵ R ^6, optionally substituted C ₁ -C ₆ alkyl which is substituted, if C ₃ -C ₈ cycloalkyl which is substituted by 3-8 membered heterocyclic ring optionally substituted, optionally with 5 Selected from ˜10 membered heteroaryl, optionally substituted C ₅ -C ₁₀ aryl, optionally substituted C ₂ -C ₆ alkenyl, and optionally substituted C ₂ -C ₆ alkynyl Optionally substituted by one or more groups),
R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ and R ¹¹ are hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, and heterocycle (each of which, except for hydrogen, halo, -OH, -O (C ₁ ~C _{4 alkyl), - CN, C 1 ~C} 4 _{alkyl, -NH 2, -NH (C 1} ~C 4 _{alkyl), - N (C 1 ~C} 4 alkyl) ( C ₁ -C ₄ alkyl), - C (O) NH 2, -C (O) NH (C 1 ~C 4 alkyl), - C (O) N (C 1 ~C 4 alkyl) (C ₁ -C ₄ alkyl), - C (O) ( C 1 ~C 4 alkyl), - NHC (O) ( C 1 ~C 4 _{alkyl), - N (C 1 ~C} 4 _{alkyl) C (O) (C 1} ~ C _{4 alkyl), - S (O) n} NH 2, -S (O) n NH (C 1 ~C 4 _{alkyl), - S (O) n} n (C 1 ~C 4 alkyl) (C ₁ -C ₄ alkyl), -S (O) _n (C ₁ -C ₄ alkyl), -NHS (O) _n (C ₁ -C ₄ alkyl), -N (C ₁ -C ₄ alkyl) S (O) _n ( C ₁ -C ₄ alkyl), optionally C ₃ -C ₈ cycloalkyl are substituted, and heterocyclic (C ₁ -C ₄ alkyl 3-8 membered optionally substituted is Optionally substituted by one or more groups selected from: optionally substituted by, halo, -OH, -OMe, or -CN, or
Or R ⁵ and R ⁶ , R ⁵ and R ⁷ , R ⁵ and R ⁸ , R ⁵ and R ⁹ , and R ⁵ and R ¹⁰ together with the atoms to which they are attached form a ring It can be, the ring, _{halo, -OH, -O (C 1 ~C} 4 _{alkyl), - CN, C 1 ~C} 4 _{alkyl, -NH 2, -NH (C 1} ~C 4 alkyl), - N (C ₁ -C ₄ alkyl) (C ₁ ~C ₄ alkyl), - C (O) NH 2, -C (O) NH (C 1 ~C 4 alkyl), - C (O) N (C 1 ~ C ₄ alkyl) (C ₁ ~C ₄ alkyl), - C (O) ( C 1 ~C 4 alkyl), - NHC (O) ( C 1 ~C 4 _{alkyl), - N (C 1 ~C} 4 alkyl _{) C (O) (C 1} ~C 4 _{alkyl), - S (O) n} NH 2, -S (O) n NH (C 1 ~C 4 _{alkyl), - S (O) n} n (C 1 ~ C ₄ alkyl) (C ₁ ~C _{4 alkyl), - S (O) n} (C 1 ~C 4 _{alkyl), - NHS (O) n} (C 1 ~C 4 alkyl), - n (C ₁ ~C ₄ alkyl) S (O) _n (C ₁ -C ₄ alkyl), optionally substituted C ₃ -C ₈ cycloalkyl, and optionally substituted 3-8 membered heterocycle (C ₁ -C ₄ alkyl is halo, -OH Optionally substituted by one or more groups selected from: optionally substituted by-, --OMe, or --CN.

In some embodiments, R ² is phenyl, naphthyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, pyrazolyl, imidazolinyl, oxazolyl, isoxazolyl, thiazolyl, thienyl, furyl, benzofuryl, benzothienyl, benzimidazolinyl, indolyl , Indazolyl, quinolinyl and indanyl, indolinyl, indoline-2-one, 2,3-dihydrobenzofuryl, benzo [d] [1,3] dioxolyl, and 1,2,3,4-tetrahydroquinolinyl, chroman 2,3-dihydrobenzo [b] [1,4] dioxinyl, 3,4-dihydro-2H-benzo [b] [1,4] oxazinyl, isochroman, 1,3-dihydroisobenzofuryl, 1H-benzo [d] [1,3] oxazine-2 (4H) -onyl (each of which is halo, —NR ⁵ R ⁶ , —OR ⁷ , —S (O) _n R ⁸ , —C (O) R ⁹ , -C (O) OR ⁷ , -CN, -C (O) NR ⁵ R ⁶ , -NR ⁵ C (O) R ⁹ , -NR ⁵ S (O) _n R ⁸ , -NR ⁵ S (O) _n NR ¹⁰ R ¹¹ , -NR ⁵ C (O) OR ⁷ , -NR ⁵ C (O) NR ¹⁰ R ¹¹ , -NO ₂ And —S (O) _n NR ⁵ R ⁶ , or methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, and t-butyl, cyclopropyl, cyclobutyl, cyclopentyl, Cyclopentenyl, cyclohexyl, cyclohexenyl, pyrrolidinyl, tetrahydrofuryl, tetrahydropyranyl, piperidinyl, piperazinyl, morpholinyl, homomorpholinyl, thiomorpholinyl, diazepanyl, oxazepanyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, pyrazolyl, imidazolyl, azolyl , Thienyl, furyl, benzofuryl, benzothienyl, benzimidazolinyl, indolyl, indazolyl, key Riniru, phenyl, and naphthyl (each of these is ^{halo, -NR 5 R 6, -OR 7} , -S (O) n R 8, -C (O) R 9, -C (O) OR 7, - CN, -C (O) NR ⁵ R ⁶ , -NR ⁵ C (O) R ⁹ , -NR ⁵ S (O) _n R ⁸ , -NR ⁵ S (O) _n NR ¹⁰ R ¹¹ , -NR ⁵ C (O) OR ⁷ , —NR ⁵ C (O) NR ¹⁰ R ¹¹ , —NO ₂ , —S (O) _n NR ⁵ R ⁶ , optionally substituted lower alkyl, optionally substituted cycloalkyl One or more selected from: an optionally substituted heterocycle, an optionally substituted heteroaryl, an optionally substituted aryl, an optionally substituted alkenyl, and an optionally substituted alkynyl Optionally substituted by one or more groups selected from) optionally substituted by a group of
R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ and R ¹¹ are hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, and heterocycle (each of which, except for hydrogen, halo, -OH, -O (C ₁ ~C _{4 alkyl), - CN, C 1 ~C} 4 _{alkyl, -NH 2, -NH (C 1} ~C 4 _{alkyl), - N (C 1 ~C} 4 alkyl) ( C ₁ -C ₄ alkyl), - C (O) NH 2, -C (O) NH (C 1 ~C 4 alkyl), - C (O) N (C 1 ~C 4 alkyl) (C ₁ -C ₄ alkyl), - C (O) ( C 1 ~C 4 alkyl), - NHC (O) ( C 1 ~C 4 _{alkyl), - N (C 1 ~C} 4 _{alkyl) C (O) (C 1} ~ C _{4 alkyl), - S (O) n} NH 2, -S (O) n NH (C 1 ~C 4 _{alkyl), - S (O) n} n (C 1 ~C 4 alkyl) (C ₁ -C ₄ alkyl), -S (O) _n (C ₁ -C ₄ alkyl), -NHS (O) _n (C ₁ -C ₄ alkyl), -N (C ₁ -C ₄ alkyl) S (O) _n ( C ₁ -C ₄ alkyl), optionally C ₃ -C ₈ cycloalkyl are substituted, and heterocyclic (C ₁ -C ₄ alkyl 3-8 membered optionally substituted is Optionally substituted by one or more groups selected from: optionally substituted by, halo, -OH, -OMe, or -CN, or
Or R ⁵ and R ⁶ , R ⁵ and R ⁷ , R ⁵ and R ⁸ , R ⁵ and R ⁹ , and R ⁵ and R ¹⁰ together with the atoms to which they are attached form a ring It can be, the ring, _{halo, -OH, -O (C 1 ~C} 4 _{alkyl), - CN, C 1 ~C} 4 _{alkyl, -NH 2, -NH (C 1} ~C 4 alkyl), - N (C ₁ -C ₄ alkyl) (C ₁ ~C ₄ alkyl), - C (O) NH 2, -C (O) NH (C 1 ~C 4 alkyl), - C (O) N (C 1 ~ C ₄ alkyl) (C ₁ ~C ₄ alkyl), - C (O) ( C 1 ~C 4 alkyl), - NHC (O) ( C 1 ~C 4 _{alkyl), - N (C 1 ~C} 4 alkyl _{) C (O) (C 1} ~C 4 _{alkyl), - S (O) n} NH 2, -S (O) n NH (C 1 ~C 4 _{alkyl), - S (O) n} n (C 1 ~ C ₄ alkyl) (C ₁ ~C _{4 alkyl), - S (O) n} (C 1 ~C 4 _{alkyl), - NHS (O) n} (C 1 ~C 4 alkyl), - n (C ₁ ~C ₄ alkyl) S (O) _n (C ₁ -C ₄ alkyl), optionally substituted C ₃ -C ₈ cycloalkyl, and optionally substituted 3-8 membered heterocycle (C ₁ -C ₄ alkyl is halo, -OH Optionally substituted by one or more groups selected from: optionally substituted by-, --OMe, or --CN.

In some embodiments, R ² is

(各々は、ハロ、-NR⁵R⁶、-OR⁷、-S(O)_nR⁸、-C(O)R⁹、-C(O)OR⁷、-CN、-C(O)NR⁵R⁶、-NR⁵C(O)R⁹、-NR⁵S(O)_nR⁸、-NR⁵S(O)_nNR¹⁰R¹¹、-NR⁵C(O)OR⁷、-NR⁵C(O)NR¹⁰R¹¹、-NO₂、及び-S(O)_nNR⁵R⁶から選択される、又はメチル、エチル、n-プロピル、i-プロピル、n-ブチル、i-ブチル、及びt-ブチル、シクロプロピル、シクロブチル、シクロペンチル、シクロペンテニル、シクロヘキシル、シクロヘキセニル、ピロリジニル、テトラヒドロフリル、テトラヒドロピラニル、ピペリジニル、ピペラジニル、モルホリニル、ホモモルホリニル、チオモルホリニル、ジアゼパニル、オキサゼパニル、ピリジル、ピリミジニル、ピラジニル、ピリダジニル、ピロリル、ピラゾリル、イミダゾリニル、オキサゾリル、イソオキサゾリル、チアゾリル、チエニル、フリル、ベンゾフリル、ベンゾチエニル、ベンゾイミダゾリニル、インドリル、インダゾリル、キノリニル、フェニル、及びナフチル(これらの各々は、ハロ、-NR⁵R⁶、-OR⁷、-S(O)_nR⁸、-C(O)R⁹、-C(O)OR⁷、-CN、-C(O)NR⁵R⁶、-NR⁵C(O)R⁹、-NR⁵S(O)_nR⁸、-NR⁵S(O)_nNR¹⁰R¹¹、-NR⁵C(O)OR⁷、-NR⁵C(O)NR¹⁰R¹¹、-NO₂、-S(O)_nNR⁵R⁶、場合により置換されている低級アルキル、場合により置換されているシクロアルキル、場合により置換されている複素環、場合により置換されているヘテロアリール、場合により置換されているアリール、場合により置換されているアルケニル、及び場合により置換されているアルキニルから選択される1つ以上の基により場合により置換されている)から選択される1つ以上の基により場合により置換されている)から選択され、
R⁵、R⁶、R⁷、R⁸、R⁹、R¹⁰及びR¹¹は、水素、アルキル、シクロアルキル、アリール、ヘテロアリール、及び複素環(これらの各々は、水素を除いて、ハロ、-OH、-O(C₁〜C₄アルキル)、-CN、C₁〜C₄アルキル、-NH₂、-NH(C₁〜C₄アルキル)、-N(C₁〜C₄アルキル)(C₁〜C₄アルキル)、-C(O)NH₂、-C(O)NH(C₁〜C₄アルキル)、-C(O)N(C₁〜C₄アルキル)(C₁〜C₄アルキル)、-C(O)(C₁〜C₄アルキル)、-NHC(O)(C₁〜C₄アルキル)、-N(C₁〜C₄アルキル)C(O)(C₁〜C₄アルキル)、-S(O)_nNH₂、-S(O)_nNH(C₁〜C₄アルキル)、-S(O)_nN(C₁〜C₄アルキル)(C₁〜C₄アルキル)、-S(O)_n(C₁〜C₄アルキル)、-NHS(O)_n(C₁〜C₄アルキル)、-N(C₁〜C₄アルキル)S(O)_n(C₁〜C₄アルキル)、場合により置換されているC₃〜C₈シクロアルキル、及び場合により置換されている3〜8員の複素環(C₁〜C₄アルキルは、ハロ、-OH、-OMe、又は-CNにより場合により置換されている)から選択される1つ以上の基により場合により置換されている)から独立して選択されるか、
又はR⁵とR⁶、R⁵とR⁷、R⁵とR⁸、R⁵とR⁹、及びR⁵とR¹⁰は、それらが結合している原子と一緒になって環を形成することができ、この環は、ハロ、-OH、-O(C₁〜C₄アルキル)、-CN、C₁-C₄アルキル、-NH₂、-NH(C₁〜C₄アルキル)、-N(C₁〜C₄アルキル)(C₁〜C₄アルキル)、-C(O)NH₂、-C(O)NH(C₁〜C₄アルキル)、-C(O)N(C₁〜C₄アルキル)(C₁〜C₄アルキル)、-C(O)(C₁〜C₄アルキル)、-NHC(O)(C₁〜C₄アルキル)、-N(C₁〜C₄アルキル)C(O)(C₁〜C₄アルキル)、-S(O)_nNH₂、-S(O)_nNH(C₁〜C₄アルキル)、-S(O)_nN(C₁〜C₄アルキル)(C₁〜C₄アルキル)、-S(O)_n(C₁〜C₄アルキル)、-NHS(O)_n(C₁〜C₄アルキル)、-N(C₁〜C₄アルキル)S(O)_n(C₁〜C₄アルキル)、場合により置換されているC₃〜C₈シクロアルキル、及び場合により置換されている3〜8員の複素環(C₁〜C₄アルキルは、ハロ、-OH、-OMe、又は-CNにより場合により置換されている)から選択される1つ以上の基により場合により置換されている。

(Each is halo, -NR ⁵ R ⁶ , -OR ⁷ , -S (O) _n R ⁸ , -C (O) R ⁹ , -C (O) OR ⁷ , -CN, -C (O) NR ⁵ R ⁶ , -NR ⁵ C (O) R ⁹ , -NR ⁵ S (O) _n R ⁸ , -NR ⁵ S (O) _n NR ¹⁰ R ¹¹ , -NR ⁵ C (O) OR ⁷ , -NR ⁵ C (O) NR ¹⁰ R ¹¹ , —NO ₂ , and —S (O) _n NR ⁵ R ⁶ , or methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl , And t-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, pyrrolidinyl, tetrahydrofuryl, tetrahydropyranyl, piperidinyl, piperazinyl, morpholinyl, homomorpholinyl, thiomorpholinyl, diazepanyl, oxazepanyl, pyridinyl, pyrimidinyl, pyrazinyl, Pyridazinyl, pyrrolyl, pyrazolyl, imidazolinyl, oxazolyl, isoxazolyl, thiazolyl, thienyl, furyl, Nzofuriru, benzothienyl, benzimidazolinyl, indolyl, indazolyl, quinolinyl, phenyl, and naphthyl (each of these is ^{halo, -NR 5 R 6, -OR 7} , -S (O) n R 8, -C ( O) R ⁹ , -C (O) OR ⁷ , -CN, -C (O) NR ⁵ R ⁶ , -NR ⁵ C (O) R ⁹ , -NR ⁵ S (O) _n R ⁸ , -NR ⁵ S (O) _n NR ¹⁰ R ¹¹ , -NR ⁵ C (O) OR ⁷ , -NR ⁵ C (O) NR ¹⁰ R ¹¹ , -NO ₂ , -S (O) _n NR ⁵ R ⁶ , optionally substituted Lower alkyl, optionally substituted cycloalkyl, optionally substituted heterocycle, optionally substituted heteroaryl, optionally substituted aryl, optionally substituted alkenyl, and Optionally substituted by one or more groups selected from (optionally substituted by one or more groups selected from optionally substituted alkynyl),
R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ and R ¹¹ are hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, and heterocycle (each of which, except for hydrogen, halo, -OH, -O (C ₁ ~C _{4 alkyl), - CN, C 1 ~C} 4 _{alkyl, -NH 2, -NH (C 1} ~C 4 _{alkyl), - N (C 1 ~C} 4 alkyl) ( C ₁ -C ₄ alkyl), - C (O) NH 2, -C (O) NH (C 1 ~C 4 alkyl), - C (O) N (C 1 ~C 4 alkyl) (C ₁ -C ₄ alkyl), - C (O) ( C 1 ~C 4 alkyl), - NHC (O) ( C 1 ~C 4 _{alkyl), - N (C 1 ~C} 4 _{alkyl) C (O) (C 1} ~ C _{4 alkyl), - S (O) n} NH 2, -S (O) n NH (C 1 ~C 4 _{alkyl), - S (O) n} n (C 1 ~C 4 alkyl) (C ₁ -C ₄ alkyl), -S (O) _n (C ₁ -C ₄ alkyl), -NHS (O) _n (C ₁ -C ₄ alkyl), -N (C ₁ -C ₄ alkyl) S (O) _n ( C ₁ -C ₄ alkyl), optionally C ₃ -C ₈ cycloalkyl are substituted, and heterocyclic (C ₁ -C ₄ alkyl 3-8 membered optionally substituted is Optionally substituted by one or more groups selected from: optionally substituted by, halo, -OH, -OMe, or -CN, or
Or R ⁵ and R ⁶ , R ⁵ and R ⁷ , R ⁵ and R ⁸ , R ⁵ and R ⁹ , and R ⁵ and R ¹⁰ together with the atoms to which they are attached form a ring It can be, the ring, _{halo, -OH, -O (C 1 ~C} 4 _{alkyl), - CN, C 1 -C} 4 _{alkyl, -NH 2, -NH (C 1} ~C 4 alkyl), - N (C ₁ -C ₄ alkyl) (C ₁ ~C ₄ alkyl), - C (O) NH 2, -C (O) NH (C 1 ~C 4 alkyl), - C (O) N (C 1 ~ C ₄ alkyl) (C ₁ ~C ₄ alkyl), - C (O) ( C 1 ~C 4 alkyl), - NHC (O) ( C 1 ~C 4 _{alkyl), - N (C 1 ~C} 4 alkyl _{) C (O) (C 1} ~C 4 _{alkyl), - S (O) n} NH 2, -S (O) n NH (C 1 ~C 4 _{alkyl), - S (O) n} n (C 1 ~ C ₄ alkyl) (C ₁ ~C _{4 alkyl), - S (O) n} (C 1 ~C 4 _{alkyl), - NHS (O) n} (C 1 ~C 4 alkyl), - n (C ₁ ~C ₄ alkyl) S (O) _n (C ₁ -C ₄ alkyl), optionally substituted C ₃ -C ₈ cycloalkyl, and optionally substituted 3-8 membered heterocycle (C ₁ -C ₄ alkyl, halo, -OH -OMe, or optionally substituted by one or more groups selected from being replaced) by optionally -CN.

In some embodiments, R ² is

(各々は、ハロ、-NR⁵R⁶、-OR⁷、-S(O)_nR⁸、-C(O)R⁹、-C(O)OR⁷、-CN、-C(O)NR⁵R⁶、-NR⁵C(O)R⁹、-NR⁵S(O)_nR⁸、-NR⁵S(O)_nNR¹⁰R¹¹、-NR⁵C(O)OR⁷、-NR⁵C(O)NR¹⁰R¹¹、-NO₂、及び-S(O)_nNR⁵R⁶から選択される、又は、メチル、エチル、n-プロピル、i-プロピル、n-ブチル、i-ブチル、及びt-ブチル、シクロプロピル、シクロブチル、シクロペンチル、シクロペンテニル、シクロヘキシル、シクロヘキセニル、ピロリジニル、テトラヒドロフリル、テトラヒドロピラニル、ピペリジニル、ピペラジニル、モルホリニル、ホモモルホリニル、チオモルホリニル、ジアゼパニル、オキサゼパニル、ピリジル、ピリミジニル、ピラジニル、ピリダジニル、ピロリル、ピラゾリル、イミダゾリニル、オキサゾリル、イソオキサゾリル、チアゾリル、チエニル、フリル、ベンゾフリル、ベンゾチエニル、ベンゾイミダゾリニル、インドリル、インダゾリル、キノリニル、フェニル、及びナフチル(これらの各々は、ハロ、-NR⁵R⁶、-OR⁷、-S(O)_nR⁸、-C(O)R⁹、-C(O)OR⁷、-CN、-C(O)NR⁵R⁶、-NR⁵C(O)R⁹、-NR⁵S(O)_nR⁸、-NR⁵S(O)_nNR¹⁰R¹¹、-NR⁵C(O)OR⁷、-NR⁵C(O)NR¹⁰R¹¹、-NO₂、-S(O)_nNR⁵R⁶、場合により置換されている低級アルキル、場合により置換されているシクロアルキル、場合により置換されている複素環、場合により置換されているヘテロアリール、場合により置換されているアリール、場合により置換されているアルケニル、及び場合により置換されているアルキニルから選択される1つ以上の基により場合により置換されている)から選択される1つ以上の基により場合により置換されている)から選択され、
R⁵、R⁶、R⁷、R⁸、R⁹、R¹⁰及びR¹¹は、水素、アルキル、シクロアルキル、アリール、ヘテロアリール、及び複素環(これらの各々は、水素を除いて、ハロ、-OH、-O(C₁〜C₄アルキル)、-CN、C₁〜C₄アルキル、-NH₂、-NH(C₁〜C₄アルキル)、-N(C₁〜C₄アルキル)(C₁〜C₄アルキル)、-C(O)NH₂、-C(O)NH(C₁〜C₄アルキル)、-C(O)N(C₁〜C₄アルキル)(C₁〜C₄アルキル)、-C(O)(C₁〜C₄アルキル)、-NHC(O)(C₁〜C₄アルキル)、-N(C₁〜C₄アルキル)C(O)(C₁〜C₄アルキル)、-S(O)_nNH₂、-S(O)_nNH(C₁〜C₄アルキル)、-S(O)_nN(C₁〜C₄アルキル)(C₁〜C₄アルキル)、-S(O)_n(C₁〜C₄アルキル)、-NHS(O)_n(C₁〜C₄アルキル)、-N(C₁〜C₄アルキル)S(O)_n(C₁〜C₄アルキル)、場合により置換されているC₃〜C₈シクロアルキル、及び場合により置換されている3〜8員の複素環(C₁〜C₄アルキルは、ハロ、-OH、-OMe、又は-CNにより場合により置換されている)から選択される1つ以上の基により場合により置換されている)から独立して選択されるか、
又はR⁵とR⁶、R⁵とR⁷、R⁵とR⁸、R⁵とR⁹、及びR⁵とR¹⁰は、それらが結合している原子と一緒になって環を形成することができ、この環は、ハロ、-OH、-O(C₁〜C₄アルキル)、-CN、C₁〜C₄アルキル、-NH₂、-NH(C₁〜C₄アルキル)、-N(C₁〜C₄アルキル)(C₁〜C₄アルキル)、-C(O)NH₂、-C(O)NH(C₁〜C₄アルキル)、-C(O)N(C₁〜C₄アルキル)(C₁〜C₄アルキル)、-C(O)(C₁〜C₄アルキル)、-NHC(O)(C₁〜C₄アルキル)、-N(C₁〜C₄アルキル)C(O)(C₁〜C₄アルキル)、-S(O)_nNH₂、-S(O)_nNH(C₁〜C₄アルキル)、-S(O)_nN(C₁〜C₄アルキル)(C₁〜C₄アルキル)、-S(O)_n(C₁〜C₄アルキル)、-NHS(O)_n(C₁〜C₄アルキル)、-N(C₁〜C₄アルキル)S(O)_n(C₁〜C₄アルキル)、場合により置換されているC₃〜C₈シクロアルキル、及び場合により置換されている3〜8員の複素環(C₁〜C₄アルキルは、ハロ、-OH、-OMe、又は-CNにより場合により置換されている)から選択される1つ以上の基により場合により置換されている。

(Each is halo, -NR ⁵ R ⁶ , -OR ⁷ , -S (O) _n R ⁸ , -C (O) R ⁹ , -C (O) OR ⁷ , -CN, -C (O) NR ⁵ R ⁶ , -NR ⁵ C (O) R ⁹ , -NR ⁵ S (O) _n R ⁸ , -NR ⁵ S (O) _n NR ¹⁰ R ¹¹ , -NR ⁵ C (O) OR ⁷ , -NR ⁵ C (O) NR ¹⁰ R ¹¹ , —NO ₂ , and —S (O) _n NR ⁵ R ⁶ , or methyl, ethyl, n-propyl, i-propyl, n-butyl, i- Butyl and t-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, pyrrolidinyl, tetrahydrofuryl, tetrahydropyranyl, piperidinyl, piperazinyl, morpholinyl, homomorpholinyl, thiomorpholinyl, diazepanyl, oxazepanyl, pyridinyl, pyridinyl, pyrazinyl , Pyridazinyl, pyrrolyl, pyrazolyl, imidazolinyl, oxazolyl, isoxazolyl, thiazolyl, thienyl, furyl Benzofuryl, benzothienyl, benzimidazolinyl, indolyl, indazolyl, quinolinyl, phenyl, and naphthyl (each of these is ^{halo, -NR 5 R 6, -OR 7} , -S (O) n R 8, -C ( O) R ⁹ , -C (O) OR ⁷ , -CN, -C (O) NR ⁵ R ⁶ , -NR ⁵ C (O) R ⁹ , -NR ⁵ S (O) _n R ⁸ , -NR ⁵ S (O) _n NR ¹⁰ R ¹¹ , -NR ⁵ C (O) OR ⁷ , -NR ⁵ C (O) NR ¹⁰ R ¹¹ , -NO ₂ , -S (O) _n NR ⁵ R ⁶ , optionally substituted Lower alkyl, optionally substituted cycloalkyl, optionally substituted heterocycle, optionally substituted heteroaryl, optionally substituted aryl, optionally substituted alkenyl, and Optionally substituted by one or more groups selected from (optionally substituted by one or more groups selected from optionally substituted alkynyl),
R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ and R ¹¹ are hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, and heterocycle (each of which, except for hydrogen, halo, -OH, -O (C ₁ ~C _{4 alkyl), - CN, C 1 ~C} 4 _{alkyl, -NH 2, -NH (C 1} ~C 4 _{alkyl), - N (C 1 ~C} 4 alkyl) ( C ₁ -C ₄ alkyl), - C (O) NH 2, -C (O) NH (C 1 ~C 4 alkyl), - C (O) N (C 1 ~C 4 alkyl) (C ₁ -C ₄ alkyl), - C (O) ( C 1 ~C 4 alkyl), - NHC (O) ( C 1 ~C 4 _{alkyl), - N (C 1 ~C} 4 _{alkyl) C (O) (C 1} ~ C _{4 alkyl), - S (O) n} NH 2, -S (O) n NH (C 1 ~C 4 _{alkyl), - S (O) n} n (C 1 ~C 4 alkyl) (C ₁ -C ₄ alkyl), -S (O) _n (C ₁ -C ₄ alkyl), -NHS (O) _n (C ₁ -C ₄ alkyl), -N (C ₁ -C ₄ alkyl) S (O) _n ( C ₁ -C ₄ alkyl), optionally C ₃ -C ₈ cycloalkyl are substituted, and heterocyclic (C ₁ -C ₄ alkyl 3-8 membered optionally substituted is Optionally substituted by one or more groups selected from: optionally substituted by, halo, -OH, -OMe, or -CN, or
Or R ⁵ and R ⁶ , R ⁵ and R ⁷ , R ⁵ and R ⁸ , R ⁵ and R ⁹ , and R ⁵ and R ¹⁰ together with the atoms to which they are attached form a ring It can be, the ring, _{halo, -OH, -O (C 1 ~C} 4 _{alkyl), - CN, C 1 ~C} 4 _{alkyl, -NH 2, -NH (C 1} ~C 4 alkyl), - N (C ₁ -C ₄ alkyl) (C ₁ ~C ₄ alkyl), - C (O) NH 2, -C (O) NH (C 1 ~C 4 alkyl), - C (O) N (C 1 ~ C ₄ alkyl) (C ₁ ~C ₄ alkyl), - C (O) ( C 1 ~C 4 alkyl), - NHC (O) ( C 1 ~C 4 _{alkyl), - N (C 1 ~C} 4 alkyl _{) C (O) (C 1} ~C 4 _{alkyl), - S (O) n} NH 2, -S (O) n NH (C 1 ~C 4 _{alkyl), - S (O) n} n (C 1 ~ C ₄ alkyl) (C ₁ ~C _{4 alkyl), - S (O) n} (C 1 ~C 4 _{alkyl), - NHS (O) n} (C 1 ~C 4 alkyl), - n (C ₁ ~C ₄ alkyl) S (O) _n (C ₁ -C ₄ alkyl), optionally substituted C ₃ -C ₈ cycloalkyl, and optionally substituted 3-8 membered heterocycle (C ₁ -C ₄ alkyl is halo, -OH Optionally substituted by one or more groups selected from: optionally substituted by-, --OMe, or --CN.

In some embodiments, R ² is

(これは、ハロ、-NR⁵R⁶、-OR⁷、-S(O)_nR⁸、-C(O)R⁹、-C(O)OR⁷、-CN、-C(O)NR⁵R⁶、-NR⁵C(O)R⁹、-NR⁵S(O)_nR⁸、-NR⁵S(O)_nNR¹⁰R¹¹、-NR⁵C(O)OR⁷、-NR⁵C(O)NR¹⁰R¹¹、-NO₂、及び-S(O)_nNR⁵R⁶から選択される、又はメチル、エチル、n-プロピル、i-プロピル、n-ブチル、i-ブチル、及びt-ブチル、シクロプロピル、シクロブチル、シクロペンチル、シクロペンテニル、シクロヘキシル、シクロヘキセニル、ピロリジニル、テトラヒドロフリル、テトラヒドロピラニル、ピペリジニル、ピペラジニル、モルホリニル、ホモモルホリニル、チオモルホリニル、ジアゼパニル、オキサゼパニル、ピリジル、ピリミジニル、ピラジニル、ピリダジニル、ピロリル、ピラゾリル、イミダゾリニル、オキサゾリル、イソオキサゾリル、チアゾリル、チエニル、フリル、ベンゾフリル、ベンゾチエニル、ベンゾイミダゾリニル、インドリル、インダゾリル、キノリニル、フェニル、及びナフチル(これらの各々は、ハロ、-NR⁵R⁶、-OR⁷、-S(O)_nR⁸、-C(O)R⁹、-C(O)OR⁷、-CN、-C(O)NR⁵R⁶、-NR⁵C(O)R⁹、-NR⁵S(O)_nR⁸、-NR⁵S(O)_nNR¹⁰R¹¹、-NR⁵C(O)OR⁷、-NR⁵C(O)NR¹⁰R¹¹、-NO₂、-S(O)_nNR⁵R⁶、場合により置換されている低級アルキル、場合により置換されているシクロアルキル、場合により置換されている複素環、場合により置換されているヘテロアリール、場合により置換されているアリール、場合により置換されているアルケニル、及び場合により置換されているアルキニルから選択される1つ以上の基により場合により置換されている)から選択される1つ以上の基により場合により置換されている)であり、
R⁵、R⁶、R⁷、R⁸、R⁹、R¹⁰及びR¹¹は、水素、アルキル、シクロアルキル、アリール、ヘテロアリール、及び複素環(これらの各々は、水素を除いて、ハロ、-OH、-O(C₁〜C₄アルキル)、-CN、C₁〜C₄アルキル、-NH₂、-NH(C₁〜C₄アルキル)、-N(C₁〜C₄アルキル)(C₁〜C₄アルキル)、-C(O)NH₂、-C(O)NH(C₁〜C₄アルキル)、-C(O)N(C₁〜C₄アルキル)(C₁〜C₄アルキル)、-C(O)(C₁〜C₄アルキル)、-NHC(O)(C₁〜C₄アルキル)、-N(C₁〜C₄アルキル)C(O)(C₁〜C₄アルキル)、-S(O)_nNH₂、-S(O)_nNH(C₁〜C₄アルキル)、-S(O)_nN(C₁〜C₄アルキル)(C₁〜C₄アルキル)、-S(O)_n(C₁〜C₄アルキル)、-NHS(O)_n(C₁〜C₄アルキル)、-N(C₁〜C₄アルキル)S(O)_n(C₁〜C₄アルキル)、場合により置換されているC₃〜C₈シクロアルキル、及び場合により置換されている3〜8員の複素環(C₁〜C₄アルキルは、ハロ、-OH、-OMe、又は-CNにより場合により置換されている)から選択される1つ以上の基により場合により置換されている)から独立して選択されるか、
又はR⁵とR⁶、R⁵とR⁷、R⁵とR⁸、R⁵とR⁹、及びR⁵とR¹⁰は、それらが結合している原子と一緒になって環を形成することができ、この環は、ハロ、-OH、-O(C₁〜C₄アルキル)、-CN、C₁〜C₄アルキル、-NH₂、-NH(C₁〜C₄アルキル)、-N(C₁〜C₄アルキル)(C₁〜C₄アルキル)、-C(O)NH₂、-C(O)NH(C₁〜C₄アルキル)、-C(O)N(C₁〜C₄アルキル)(C₁〜C₄アルキル)、-C(O)(C₁〜C₄アルキル)、-NHC(O)(C₁〜C₄アルキル)、-N(C₁〜C₄アルキル)C(O)(C₁〜C₄アルキル)、-S(O)_nNH₂、-S(O)_nNH(C₁〜C₄アルキル)、-S(O)_nN(C₁〜C₄アルキル)(C₁〜C₄アルキル)、-S(O)_n(C₁〜C₄アルキル)、-NHS(O)_n(C₁〜C₄アルキル)、-N(C₁〜C₄アルキル)S(O)_n(C₁〜C₄アルキル)、場合により置換されているC₃〜C₈シクロアルキル、及び場合により置換されている3〜8員の複素環(C₁〜C₄アルキルは、ハロ、-OH、-OMe、又は-CNにより場合により置換されている)から選択される1つ以上の基により場合により置換されている。

(This is halo, -NR ⁵ R ⁶ , -OR ⁷ , -S (O) _n R ⁸ , -C (O) R ⁹ , -C (O) OR ⁷ , -CN, -C (O) NR ⁵ R ⁶ , -NR ⁵ C (O) R ⁹ , -NR ⁵ S (O) _n R ⁸ , -NR ⁵ S (O) _n NR ¹⁰ R ¹¹ , -NR ⁵ C (O) OR ⁷ , -NR ⁵ C (O) NR ¹⁰ R ¹¹ , —NO ₂ , and —S (O) _n NR ⁵ R ⁶ , or methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl , And t-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, pyrrolidinyl, tetrahydrofuryl, tetrahydropyranyl, piperidinyl, piperazinyl, morpholinyl, homomorpholinyl, thiomorpholinyl, diazepanyl, oxazepanyl, pyridinyl, pyrimidinyl, pyrazinyl, Pyridazinyl, pyrrolyl, pyrazolyl, imidazolinyl, oxazolyl, isoxazolyl, thiazolyl, thienyl, furyl, Nzofuriru, benzothienyl, benzimidazolinyl, indolyl, indazolyl, quinolinyl, phenyl, and naphthyl (each of these is ^{halo, -NR 5 R 6, -OR 7} , -S (O) n R 8, -C ( O) R ⁹ , -C (O) OR ⁷ , -CN, -C (O) NR ⁵ R ⁶ , -NR ⁵ C (O) R ⁹ , -NR ⁵ S (O) _n R ⁸ , -NR ⁵ S (O) _n NR ¹⁰ R ¹¹ , -NR ⁵ C (O) OR ⁷ , -NR ⁵ C (O) NR ¹⁰ R ¹¹ , -NO ₂ , -S (O) _n NR ⁵ R ⁶ , optionally substituted Lower alkyl, optionally substituted cycloalkyl, optionally substituted heterocycle, optionally substituted heteroaryl, optionally substituted aryl, optionally substituted alkenyl, and Optionally substituted by one or more groups selected from) optionally substituted by one or more groups selected from optionally substituted alkynyl,
R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ and R ¹¹ are hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, and heterocycle (each of which, except for hydrogen, halo, -OH, -O (C ₁ ~C _{4 alkyl), - CN, C 1 ~C} 4 _{alkyl, -NH 2, -NH (C 1} ~C 4 _{alkyl), - N (C 1 ~C} 4 alkyl) ( C ₁ -C ₄ alkyl), - C (O) NH 2, -C (O) NH (C 1 ~C 4 alkyl), - C (O) N (C 1 ~C 4 alkyl) (C ₁ -C ₄ alkyl), - C (O) ( C 1 ~C 4 alkyl), - NHC (O) ( C 1 ~C 4 _{alkyl), - N (C 1 ~C} 4 _{alkyl) C (O) (C 1} ~ C _{4 alkyl), - S (O) n} NH 2, -S (O) n NH (C 1 ~C 4 _{alkyl), - S (O) n} n (C 1 ~C 4 alkyl) (C ₁ -C ₄ alkyl), -S (O) _n (C ₁ -C ₄ alkyl), -NHS (O) _n (C ₁ -C ₄ alkyl), -N (C ₁ -C ₄ alkyl) S (O) _n ( C ₁ -C ₄ alkyl), optionally C ₃ -C ₈ cycloalkyl are substituted, and heterocyclic (C ₁ -C ₄ alkyl 3-8 membered optionally substituted is Optionally substituted by one or more groups selected from: optionally substituted by, halo, -OH, -OMe, or -CN, or
Or R ⁵ and R ⁶ , R ⁵ and R ⁷ , R ⁵ and R ⁸ , R ⁵ and R ⁹ , and R ⁵ and R ¹⁰ together with the atoms to which they are attached form a ring It can be, the ring, _{halo, -OH, -O (C 1 ~C} 4 _{alkyl), - CN, C 1 ~C} 4 _{alkyl, -NH 2, -NH (C 1} ~C 4 alkyl), - N (C ₁ -C ₄ alkyl) (C ₁ ~C ₄ alkyl), - C (O) NH 2, -C (O) NH (C 1 ~C 4 alkyl), - C (O) N (C 1 ~ C ₄ alkyl) (C ₁ ~C ₄ alkyl), - C (O) ( C 1 ~C 4 alkyl), - NHC (O) ( C 1 ~C 4 _{alkyl), - N (C 1 ~C} 4 alkyl _{) C (O) (C 1} ~C 4 _{alkyl), - S (O) n} NH 2, -S (O) n NH (C 1 ~C 4 _{alkyl), - S (O) n} n (C 1 ~ C ₄ alkyl) (C ₁ ~C _{4 alkyl), - S (O) n} (C 1 ~C 4 _{alkyl), - NHS (O) n} (C 1 ~C 4 alkyl), - n (C ₁ ~C ₄ alkyl) S (O) _n (C ₁ -C ₄ alkyl), optionally substituted C ₃ -C ₈ cycloalkyl, and optionally substituted 3-8 membered heterocycle (C ₁ -C ₄ alkyl is halo, -OH Optionally substituted by one or more groups selected from: optionally substituted by-, --OMe, or --CN.

  In some embodiments, L is a bond.

In some embodiments, L is —CH ₂ —.

In some embodiments, L is —CH ₂ CH ₂ —.

In some embodiments, W is C ₃ -C ₈ cycloalkyl, 3-8 membered heterocycle, C ₅ -C ₁₀ aryl, or 5-10 membered heteroaryl.

  In some embodiments, W is cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, pyrrolidinyl, tetrahydrofuryl, tetrahydropyranyl, piperidinyl, piperazinyl, morpholinyl, homomorpholinyl, thiomorpholinyl, phenyl, naphthyl, pyridyl, Pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, pyrazolyl, imidazolinyl, oxazolyl, isoxazolyl, thiazolyl, thienyl, furyl, benzofuryl, benzothienyl, benzoimidazolinyl, indolyl, indazolyl, or quinolinyl.

  In some embodiments, W is cyclohexyl, tetrahydrofuryl, tetrahydropyranyl, piperidinyl, morpholinyl, phenyl, or pyrazolyl.

  In some embodiments, W is tetrahydrofuryl.

  In some embodiments, W is

である。

It is.

  In some embodiments, W is tetrahydropyranyl.

  In some embodiments, W is

である。

It is.

  In some embodiments, W is morpholinyl.

In some embodiments, W is morpholinyl substituted with R ³ on the nitrogen atom.

In some embodiments, W is substituted on the nitrogen atom with R ³

であり、
R³は、-Lx-S(O)_nR⁸、-Lx-C(O)R⁹、-S(O)_n-Lx-R⁸、-C(O)-Lx-R⁹、-Lx-NR⁵C(O)R⁹、-Lx-NR⁵S(O)_nR⁸、-Lx-NR⁵C(O)NR¹⁰R¹¹、-Lx-NR⁵S(O)_nNR¹⁰R¹¹、-Lx-C(O)NR⁵R⁶、-Lx-S(O)_nNR⁵R⁶から独立して選択され、
R⁵、R⁶、R⁷、R⁸及びR⁹は、水素、アルキル、シクロアルキル、アリール、ヘテロアリール、及び複素環(これらの各々は、水素を除いて、ハロ、-OH、-O(C₁〜C₄アルキル)、-CN、C₁〜C₄アルキル、-NH₂、-NH(C₁〜C₄アルキル)、-N(C₁〜C₄アルキル)(C₁〜C₄アルキル)、-C(O)NH₂、-C(O)NH(C₁〜C₄アルキル)、-C(O)N(C₁〜C₄アルキル)(C₁〜C₄アルキル)、-C(O)(C₁〜C₄アルキル)、-NHC(O)(C₁〜C₄アルキル)、-N(C₁〜C₄アルキル)C(O)(C₁〜C₄アルキル)、-S(O)_nNH₂、-S(O)_nNH(C₁〜C₄アルキル)、-S(O)_nN(C₁〜C₄アルキル)(C₁〜C₄アルキル)、-S(O)_n(C₁〜C₄アルキル)、-NHS(O)_n(C₁〜C₄アルキル)、-N(C₁〜C₄アルキル)S(O)_n(C₁〜C₄アルキル)、場合により置換されているC₃〜C₈シクロアルキル、及び場合により置換されている3〜8員の複素環(C₁〜C₄アルキルは、ハロ、-OH、-OMe、又は-CNにより場合により置換されている)から選択される1つ以上の基により場合により置換されている)から独立して選択されるか、
又はR⁵とR⁶、R⁵とR⁷、R⁵とR⁸、及びR⁵とR⁹は、それらが結合している原子と一緒になって環を形成することができ、この環は、ハロ、-OH、-O(C₁〜C₄アルキル)、-CN、C₁〜C₄アルキル、-NH₂、-NH(C₁〜C₄アルキル)、-N(C₁〜C₄アルキル)(C₁〜C₄アルキル)、-C(O)NH₂、-C(O)NH(C₁〜C₄アルキル)、-C(O)N(C₁〜C₄アルキル)(C₁〜C₄アルキル)、-C(O)(C₁〜C₄アルキル)、-NHC(O)(C₁〜C₄アルキル)、-N(C₁〜C₄アルキル)C(O)(C₁〜C₄アルキル)、-S(O)_nNH₂、-S(O)_nNH(C₁〜C₄アルキル)、-S(O)_nN(C₁〜C₄アルキル)(C₁〜C₄アルキル)、-S(O)_n(C₁〜C₄アルキル)、-NHS(O)_n(C₁〜C₄アルキル)、-N(C₁〜C₄アルキル)S(O)_n(C₁〜C₄アルキル)、場合により置換されているC₃〜C₈シクロアルキル、及び場合により置換されている3〜8員の複素環(C₁〜C₄アルキルは、ハロ、-OH、-OMe、又は-CNにより場合により置換されている)から選択される1つ以上の基により場合により置換されており、
L_xは、場合により置換されているC₁〜C₆アルキレンである。

And
R ³ is -Lx-S (O) _n R ⁸ , -Lx-C (O) R ⁹ , -S (O) _n -Lx-R ⁸ , -C (O) -Lx-R ⁹ , -Lx -NR ⁵ C (O) R ⁹ , -Lx-NR ⁵ S (O) _n R ⁸ , -Lx-NR ⁵ C (O) NR ¹⁰ R ¹¹ , -Lx-NR ⁵ S (O) _n NR ¹⁰ R ¹¹ , -Lx-C (O) NR ⁵ R ⁶ , independently selected from -Lx-S (O) _n NR ⁵ R ⁶ ,
R ⁵ , R ⁶ , R ⁷ , R ⁸ and R ⁹ are hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, and heterocycle (each of which, except for hydrogen, halo, —OH, —O ( C ₁ -C _{4 alkyl), - CN, C 1 ~C} 4 _{alkyl, -NH 2, -NH (C 1} ~C 4 _{alkyl), - N (C 1 ~C} 4 alkyl) (C ₁ ~C ₄ alkyl ), - C (O) NH 2, -C (O) NH (C 1 ~C 4 alkyl), - C (O) N (C 1 ~C 4 alkyl) (C ₁ ~C ₄ alkyl), - C (O) (C ₁ ~C ₄ alkyl), - NHC (O) ( C 1 ~C 4 _{alkyl), - N (C 1 ~C} 4 _{alkyl) C (O) (C 1} ~C 4 alkyl), - S (O) _n NH ₂ , -S (O) _n NH (C ₁ -C ₄ alkyl), -S (O) _n N (C ₁ -C ₄ alkyl) (C ₁ -C ₄ alkyl), -S (O) _n (C ₁ -C ₄ alkyl), -NHS (O) _n (C ₁ -C ₄ alkyl), -N (C ₁ -C ₄ alkyl) S (O) _n (C ₁ -C ₄ alkyl) ), when the heterocycle (C ₁ -C ₄ alkyl 3- to 8-membered substituted C ₃ -C ₈ cycloalkyl which is substituted, and optionally by the halo, -OH -OMe, or are independently selected from is substituted) optionally with one or more groups selected from) optionally substituted by -CN,
Or R ⁵ and R ⁶ , R ⁵ and R ⁷ , R ⁵ and R ⁸ , and R ⁵ and R ⁹ together with the atoms to which they are attached can form a ring, , _{halo, -OH, -O (C 1 ~C} 4 _{alkyl), - CN, C 1 ~C} 4 _{alkyl, -NH 2, -NH (C 1} ~C 4 _{alkyl), - N (C 1 ~C} 4 alkyl) (C ₁ ~C ₄ alkyl), - C (O) NH 2, -C (O) NH (C 1 ~C 4 alkyl), - C (O) N (C 1 ~C 4 alkyl) (C ₁ -C ₄ alkyl), - C (O) ( C 1 ~C 4 alkyl), - NHC (O) ( C 1 ~C 4 _{alkyl), - N (C 1 ~C} 4 alkyl) C (O) ( C ₁ -C _{4 alkyl), - S (O) n} NH 2, -S (O) n NH (C 1 ~C 4 _{alkyl), - S (O) n} n (C 1 ~C 4 alkyl) (C ₁ -C _{4 alkyl), - S (O) n} (C 1 ~C 4 _{alkyl), - NHS (O) n} (C 1 ~C 4 _{alkyl), - n (C 1 ~C} 4 alkyl) S (O ) _n (C ₁ ~C ₄ alkyl), heterocyclic (C ₁ -C ₄ alkyl 3- to 8-membered substituted by C ₃ -C ₈ cycloalkyl, and optionally substituted case, halo, -OH, -OMe, or Are optionally substituted by one or more groups selected from being replaced) by optionally -CN,
L _x is an optionally substituted C ₁ -C ₆ alkylene.

In some embodiments, W is substituted on the nitrogen atom with R ³

であり、
R³は、-Lx-S(O)_nR⁸、-Lx-C(O)R⁹、-S(O)_n-Lx-R⁸、-C(O)-Lx-R⁹、-Lx-NR⁵C(O)R⁹、-Lx-NR⁵S(O)_nR⁸、-Lx-NR⁵C(O)NR¹⁰R¹¹、-Lx-NR⁵S(O)_nNR¹⁰R¹¹、-Lx-C(O)NR⁵R⁶、-Lx-S(O)_nNR⁵R⁶から独立して選択され、
R⁵、R⁶、R⁷、R⁸及びR⁹は、水素、アルキル、シクロアルキル、アリール、ヘテロアリール、及び複素環(これらの各々は、水素を除いて、ハロ、-OH、-O(C₁〜C₄アルキル)、-CN、C₁〜C₄アルキル、-NH₂、-NH(C₁〜C₄アルキル)、-N(C₁〜C₄アルキル)(C₁〜C₄アルキル)、-C(O)NH₂、-C(O)NH(C₁〜C₄アルキル)、-C(O)N(C₁〜C₄アルキル)(C₁〜C₄アルキル)、-C(O)(C₁〜C₄アルキル)、-NHC(O)(C₁〜C₄アルキル)、-N(C₁〜C₄アルキル)C(O)(C₁〜C₄アルキル)、-S(O)_nNH₂、-S(O)_nNH(C₁〜C₄アルキル)、-S(O)_nN(C₁〜C₄アルキル)(C₁〜C₄アルキル)、-S(O)_n(C₁〜C₄アルキル)、-NHS(O)_n(C₁〜C₄アルキル)、-N(C₁〜C₄アルキル)S(O)_n(C₁〜C₄アルキル)、場合により置換されているC₃〜C₈シクロアルキル、及び場合により置換されている3〜8員の複素環(C₁〜C₄アルキルは、ハロ、-OH、-OMe、又は-CNにより場合により置換されている)から選択される1つ以上の基により場合により置換されている)から独立して選択されるか、
又はR⁵とR⁶、R⁵とR⁷、R⁵とR⁸、及びR⁵とR⁹は、それらが結合している原子と一緒になって環を形成することができ、この環は、ハロ、-OH、-O(C₁〜C₄アルキル)、-CN、C₁〜C₄アルキル、-NH₂、-NH(C₁〜C₄アルキル)、-N(C₁〜C₄アルキル)(C₁〜C₄アルキル)、-C(O)NH₂、-C(O)NH(C₁〜C₄アルキル)、-C(O)N(C₁〜C₄アルキル)(C₁〜C₄アルキル)、-C(O)(C₁〜C₄アルキル)、-NHC(O)(C₁〜C₄アルキル)、-N(C₁〜C₄アルキル)C(O)(C₁〜C₄アルキル)、-S(O)_nNH₂、-S(O)_nNH(C₁〜C₄アルキル)、-S(O)_nN(C₁〜C₄アルキル)(C₁〜C₄アルキル)、-S(O)_n(C₁〜C₄アルキル)、-NHS(O)_n(C₁〜C₄アルキル)、-N(C₁〜C₄アルキル)S(O)_n(C₁〜C₄アルキル)、場合により置換されているC₃〜C₈シクロアルキル、及び場合により置換されている3〜8員の複素環(C₁〜C₄アルキルは、ハロ、-OH、-OMe、又は-CNにより場合により置換されている)から選択される1つ以上の基により場合により置換されており、
L_xは、場合により置換されているC₁〜C₆アルキレンである。

And
R ³ is -Lx-S (O) _n R ⁸ , -Lx-C (O) R ⁹ , -S (O) _n -Lx-R ⁸ , -C (O) -Lx-R ⁹ , -Lx -NR ⁵ C (O) R ⁹ , -Lx-NR ⁵ S (O) _n R ⁸ , -Lx-NR ⁵ C (O) NR ¹⁰ R ¹¹ , -Lx-NR ⁵ S (O) _n NR ¹⁰ R ¹¹ , -Lx-C (O) NR ⁵ R ⁶ , independently selected from -Lx-S (O) _n NR ⁵ R ⁶ ,
R ⁵ , R ⁶ , R ⁷ , R ⁸ and R ⁹ are hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, and heterocycle (each of which, except for hydrogen, halo, —OH, —O ( C ₁ -C _{4 alkyl), - CN, C 1 ~C} 4 _{alkyl, -NH 2, -NH (C 1} ~C 4 _{alkyl), - N (C 1 ~C} 4 alkyl) (C ₁ ~C ₄ alkyl ), - C (O) NH 2, -C (O) NH (C 1 ~C 4 alkyl), - C (O) N (C 1 ~C 4 alkyl) (C ₁ ~C ₄ alkyl), - C (O) (C ₁ ~C ₄ alkyl), - NHC (O) ( C 1 ~C 4 _{alkyl), - N (C 1 ~C} 4 _{alkyl) C (O) (C 1} ~C 4 alkyl), - S (O) _n NH ₂ , -S (O) _n NH (C ₁ -C ₄ alkyl), -S (O) _n N (C ₁ -C ₄ alkyl) (C ₁ -C ₄ alkyl), -S (O) _n (C ₁ -C ₄ alkyl), -NHS (O) _n (C ₁ -C ₄ alkyl), -N (C ₁ -C ₄ alkyl) S (O) _n (C ₁ -C ₄ alkyl) ), when the heterocycle (C ₁ -C ₄ alkyl 3- to 8-membered substituted C ₃ -C ₈ cycloalkyl which is substituted, and optionally by the halo, -OH -OMe, or are independently selected from is substituted) optionally with one or more groups selected from) optionally substituted by -CN,
Or R ⁵ and R ⁶ , R ⁵ and R ⁷ , R ⁵ and R ⁸ , and R ⁵ and R ⁹ together with the atoms to which they are attached can form a ring, , _{halo, -OH, -O (C 1 ~C} 4 _{alkyl), - CN, C 1 ~C} 4 _{alkyl, -NH 2, -NH (C 1} ~C 4 _{alkyl), - N (C 1 ~C} 4 alkyl) (C ₁ ~C ₄ alkyl), - C (O) NH 2, -C (O) NH (C 1 ~C 4 alkyl), - C (O) N (C 1 ~C 4 alkyl) (C ₁ -C ₄ alkyl), - C (O) ( C 1 ~C 4 alkyl), - NHC (O) ( C 1 ~C 4 _{alkyl), - N (C 1 ~C} 4 alkyl) C (O) ( C ₁ -C _{4 alkyl), - S (O) n} NH 2, -S (O) n NH (C 1 ~C 4 _{alkyl), - S (O) n} n (C 1 ~C 4 alkyl) (C ₁ -C _{4 alkyl), - S (O) n} (C 1 ~C 4 _{alkyl), - NHS (O) n} (C 1 ~C 4 _{alkyl), - n (C 1 ~C} 4 alkyl) S (O ) _n (C ₁ ~C ₄ alkyl), heterocyclic (C ₁ -C ₄ alkyl 3- to 8-membered substituted by C ₃ -C ₈ cycloalkyl, and optionally substituted case, halo, -OH, -OMe, or Are optionally substituted by one or more groups selected from being replaced) by optionally -CN,
L _x is an optionally substituted C ₁ -C ₆ alkylene.

In some embodiments, W is substituted on the nitrogen atom with R ³

であり、
R³は、-Lx-S(O)_nR⁸、-Lx-C(O)R⁹、-S(O)_n-Lx-R⁸、-C(O)-Lx-R⁹、-Lx-NR⁵C(O)R⁹、-Lx-NR⁵S(O)_nR⁸、-Lx-NR⁵C(O)NR¹⁰R¹¹、-Lx-NR⁵S(O)_nNR¹⁰R¹¹、-Lx-C(O)NR⁵R⁶、-Lx-S(O)_nNR⁵R⁶から独立して選択され、
R⁵、R⁶、R⁷、R⁸及びR⁹は、水素、アルキル、シクロアルキル、アリール、ヘテロアリール、及び複素環(これらの各々は、水素を除いて、ハロ、-OH、-O(C₁〜C₄アルキル)、-CN、C₁〜C₄アルキル、-NH₂、-NH(C₁〜C₄アルキル)、-N(C₁〜C₄アルキル)(C₁〜C₄アルキル)、-C(O)NH₂、-C(O)NH(C₁〜C₄アルキル)、-C(O)N(C₁〜C₄アルキル)(C₁〜C₄アルキル)、-C(O)(C₁〜C₄アルキル)、-NHC(O)(C₁〜C₄アルキル)、-N(C₁〜C₄アルキル)C(O)(C₁〜C₄アルキル)、-S(O)_nNH₂、-S(O)_nNH(C₁〜C₄アルキル)、-S(O)_nN(C₁〜C₄アルキル)(C₁〜C₄アルキル)、-S(O)_n(C₁〜C₄アルキル)、-NHS(O)_n(C₁〜C₄アルキル)、-N(C₁〜C₄アルキル)S(O)_n(C₁〜C₄アルキル)、場合により置換されているC₃〜C₈シクロアルキル、及び場合により置換されている3〜8員の複素環(C₁〜C₄アルキルは、ハロ、-OH、-OMe、又は-CNにより場合により置換されている)から選択される1つ以上の基により場合により置換されている)から独立して選択されるか、
又はR⁵とR⁶、R⁵とR⁷、R⁵とR⁸、及びR⁵とR⁹は、それらが結合している原子と一緒になって環を形成することができ、この環は、ハロ、-OH、-O(C₁〜C₄アルキル)、-CN、C₁〜C₄アルキル、-NH₂、-NH(C₁〜C₄アルキル)、-N(C₁〜C₄アルキル)(C₁〜C₄アルキル)、-C(O)NH₂、-C(O)NH(C₁〜C₄アルキル)、-C(O)N(C₁〜C₄アルキル)(C₁〜C₄アルキル)、-C(O)(C₁〜C₄アルキル)、-NHC(O)(C₁〜C₄アルキル)、-N(C₁〜C₄アルキル)C(O)(C₁〜C₄アルキル)、-S(O)_nNH₂、-S(O)_nNH(C₁〜C₄アルキル)、-S(O)_nN(C₁〜C₄アルキル)(C₁〜C₄アルキル)、-S(O)_n(C₁〜C₄アルキル)、-NHS(O)_n(C₁〜C₄アルキル)、-N(C₁〜C₄アルキル)S(O)_n(C₁〜C₄アルキル)、場合により置換されているC₃〜C₈シクロアルキル、及び場合により置換されている3〜8員の複素環(C₁〜C₄アルキルは、ハロ、-OH、-OMe、又は-CNにより場合により置換されている)から選択される1つ以上の基により場合により置換されており、
L_xは、場合により置換されているC₁〜C₆アルキレンである。

And
R ³ is -Lx-S (O) _n R ⁸ , -Lx-C (O) R ⁹ , -S (O) _n -Lx-R ⁸ , -C (O) -Lx-R ⁹ , -Lx -NR ⁵ C (O) R ⁹ , -Lx-NR ⁵ S (O) _n R ⁸ , -Lx-NR ⁵ C (O) NR ¹⁰ R ¹¹ , -Lx-NR ⁵ S (O) _n NR ¹⁰ R ¹¹ , -Lx-C (O) NR ⁵ R ⁶ , independently selected from -Lx-S (O) _n NR ⁵ R ⁶ ,
R ⁵ , R ⁶ , R ⁷ , R ⁸ and R ⁹ are hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, and heterocycle (each of which, except for hydrogen, halo, —OH, —O ( C ₁ -C _{4 alkyl), - CN, C 1 ~C} 4 _{alkyl, -NH 2, -NH (C 1} ~C 4 _{alkyl), - N (C 1 ~C} 4 alkyl) (C ₁ ~C ₄ alkyl ), - C (O) NH 2, -C (O) NH (C 1 ~C 4 alkyl), - C (O) N (C 1 ~C 4 alkyl) (C ₁ ~C ₄ alkyl), - C (O) (C ₁ ~C ₄ alkyl), - NHC (O) ( C 1 ~C 4 _{alkyl), - N (C 1 ~C} 4 _{alkyl) C (O) (C 1} ~C 4 alkyl), - S (O) _n NH ₂ , -S (O) _n NH (C ₁ -C ₄ alkyl), -S (O) _n N (C ₁ -C ₄ alkyl) (C ₁ -C ₄ alkyl), -S (O) _n (C ₁ -C ₄ alkyl), -NHS (O) _n (C ₁ -C ₄ alkyl), -N (C ₁ -C ₄ alkyl) S (O) _n (C ₁ -C ₄ alkyl) ), when the heterocycle (C ₁ -C ₄ alkyl 3- to 8-membered substituted C ₃ -C ₈ cycloalkyl which is substituted, and optionally by the halo, -OH -OMe, or are independently selected from is substituted) optionally with one or more groups selected from) optionally substituted by -CN,
Or R ⁵ and R ⁶ , R ⁵ and R ⁷ , R ⁵ and R ⁸ , and R ⁵ and R ⁹ together with the atoms to which they are attached can form a ring, , _{halo, -OH, -O (C 1 ~C} 4 _{alkyl), - CN, C 1 ~C} 4 _{alkyl, -NH 2, -NH (C 1} ~C 4 _{alkyl), - N (C 1 ~C} 4 alkyl) (C ₁ ~C ₄ alkyl), - C (O) NH 2, -C (O) NH (C 1 ~C 4 alkyl), - C (O) N (C 1 ~C 4 alkyl) (C ₁ -C ₄ alkyl), - C (O) ( C 1 ~C 4 alkyl), - NHC (O) ( C 1 ~C 4 _{alkyl), - N (C 1 ~C} 4 alkyl) C (O) ( C ₁ -C _{4 alkyl), - S (O) n} NH 2, -S (O) n NH (C 1 ~C 4 _{alkyl), - S (O) n} n (C 1 ~C 4 alkyl) (C ₁ -C _{4 alkyl), - S (O) n} (C 1 ~C 4 _{alkyl), - NHS (O) n} (C 1 ~C 4 _{alkyl), - n (C 1 ~C} 4 alkyl) S (O ) _n (C ₁ ~C ₄ alkyl), heterocyclic (C ₁ -C ₄ alkyl 3- to 8-membered substituted by C ₃ -C ₈ cycloalkyl, and optionally substituted case, halo, -OH, -OMe, or Are optionally substituted by one or more groups selected from being replaced) by optionally -CN,
L _x is an optionally substituted C ₁ -C ₆ alkylene.

In some embodiments, R ³ is hydrogen, -Lx-halo, -Lx-R ⁴ , -Lx-NR ⁵ R ⁶ , -Lx-OR ⁷ , -Lx-S (O) _n R ⁸ ,- Lx-C (O) R ⁹ , -S (O) _n -Lx-R ⁸ , -C (O) -Lx-R ⁹ , -Lx-CN, -Lx-NR ⁵ C (O) R ⁹ ,- Lx-NR ⁵ S (O) _n R ⁸ , -Lx-NR ⁵ C (O) NR ¹⁰ R ¹¹ , -Lx-NR ⁵ S (O) _n NR ¹⁰ R ¹¹ , -Lx-NR ⁵ C (O) OR ⁷ , -Lx-NR ⁵ S (O) _n OR ⁷ , -NO ₂ , -Lx-C (O) NR ⁵ R ⁶ , -Lx-S (O) _n NR ⁵ R ⁶ , Oxo (= O) , optionally substituted C ₃ -C ₈ cycloalkyl substituted, optionally heterocyclic 3-8 membered substituted, if C ₅ -C ₁₀ aryl substituted by, and optionally with 5 Independently selected from ˜10 membered heteroaryl, provided that when L is methylene and W is a 5 or 6 membered heterocycle, R ³ is —Lx—NR ⁵ R ⁶ , -Lx-OR ⁷ , -Lx-S (O) _n R ⁸ , -Lx-C (O) R ⁹ , -S (O) _n -Lx-R ⁸ , -C (O) -Lx-R ⁹ , -Lx-CN, -Lx-NR ⁵ C (O) R ⁹ , -Lx-NR ⁵ S (O) _n R ⁸ , -Lx-NR ⁵ C (O) NR ¹⁰ R ¹¹ , -Lx-NR ⁵ S (O) _n NR ¹⁰ R ¹¹ , -Lx-NR ⁵ C (O) OR ⁷ , -Lx-NR ⁵ S (O) _n OR ⁷ , -NO ₂ , -Lx-C (O) NR ⁵ R ⁶ , -Lx-S (O) _n NR ⁵ R ⁶ , oxo (═O), optionally substituted C ₃ -C ₈ cycloalkyl, optionally substituted 3-8 membered heterocycle, optionally substituted C ₅ -C ₁₀ Provided that it is independently selected from aryl and optionally substituted 5-10 membered heteroaryl;
R ⁴ is an optionally substituted C ₁ -C ₄ alkyl;
R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ and R ¹¹ are hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, and heterocycle (each of which, except for hydrogen, halo, -OH, -O (C ₁ ~C _{4 alkyl), - CN, C 1 ~C} 4 _{alkyl, -NH 2, -NH (C 1} ~C 4 _{alkyl), - N (C 1 ~C} 4 alkyl) ( C ₁ -C ₄ alkyl), - C (O) NH 2, -C (O) NH (C 1 ~C 4 alkyl), - C (O) N (C 1 ~C 4 alkyl) (C ₁ -C ₄ alkyl), - C (O) ( C 1 ~C 4 alkyl), - NHC (O) ( C 1 ~C 4 _{alkyl), - N (C 1 ~C} 4 _{alkyl) C (O) (C 1} ~ C _{4 alkyl), - S (O) n} NH 2, -S (O) n NH (C 1 ~C 4 _{alkyl), - S (O) n} n (C 1 ~C 4 alkyl) (C ₁ -C ₄ alkyl), -S (O) _n (C ₁ -C ₄ alkyl), -NHS (O) _n (C ₁ -C ₄ alkyl), -N (C ₁ -C ₄ alkyl) S (O) _n ( C ₁ -C ₄ alkyl), optionally C ₃ -C ₈ cycloalkyl are substituted, and heterocyclic (C ₁ -C ₄ alkyl 3-8 membered optionally substituted is Optionally substituted by one or more groups selected from: optionally substituted by, halo, -OH, -OMe, or -CN, or
Or R ⁵ and R ⁶ , R ⁵ and R ⁷ , R ⁵ and R ⁸ , R ⁵ and R ⁹ , and R ⁵ and R ¹⁰ together with the atoms to which they are attached form a ring It can be, the ring, _{halo, -OH, -O (C 1 ~C} 4 _{alkyl), - CN, C 1 ~C} 4 _{alkyl, -NH 2, -NH (C 1} ~C 4 alkyl), - N (C ₁ -C ₄ alkyl) (C ₁ ~C ₄ alkyl), - C (O) NH 2, -C (O) NH (C 1 ~C 4 alkyl), - C (O) N (C 1 ~ C ₄ alkyl) (C ₁ ~C ₄ alkyl), - C (O) ( C 1 ~C 4 alkyl), - NHC (O) ( C 1 ~C 4 _{alkyl), - N (C 1 ~C} 4 alkyl _{) C (O) (C 1} ~C 4 _{alkyl), - S (O) n} NH 2, -S (O) n NH (C 1 ~C 4 _{alkyl), - S (O) n} n (C 1 ~ C ₄ alkyl) (C ₁ ~C _{4 alkyl), - S (O) n} (C 1 ~C 4 _{alkyl), - NHS (O) n} (C 1 ~C 4 alkyl), - n (C ₁ ~C ₄ alkyl) S (O) _n (C ₁ -C ₄ alkyl), optionally substituted C ₃ -C ₈ cycloalkyl, and optionally substituted 3-8 membered heterocycle (C ₁ -C ₄ alkyl is halo, -OH Optionally substituted by one or more groups selected from: optionally substituted by-, --OMe, or --CN;
L _x is a bond or optionally substituted C ₁ -C ₆ alkylene.

In some embodiments, R ³ is hydrogen, -Lx-halo, -Lx-R ⁴ , -Lx-NR ⁵ R ⁶ , -Lx-OR ⁷ , -Lx-S (O) _n R ⁸ ,- Lx-C (O) R ⁹ , -S (O) _n -Lx-R ⁸ , -C (O) -Lx-R ⁹ , -Lx-CN, -Lx-NR ⁵ C (O) R ⁹ ,- Lx-NR ⁵ S (O) _n R ⁸ , -Lx-NR ⁵ C (O) NR ¹⁰ R ¹¹ , -Lx-NR ⁵ S (O) _n NR ¹⁰ R ¹¹ , -Lx-NR ⁵ C (O) OR ⁷ , -Lx-NR ⁵ S (O) _n OR ⁷ , -NO ₂ , -Lx-C (O) NR ⁵ R ⁶ , -Lx-S (O) _n NR ⁵ R ⁶ , Oxo (= O) Or independently selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, pyrrolidinyl, tetrahydrofuryl, tetrahydropyranyl, piperidinyl, piperazinyl, morpholinyl, homomorpholinyl, thiomorpholinyl, diazepanyl, oxazepanyl, phenyl, Naphthyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, pyrazolyl, imidazolinyl, oxazo Le, isoxazolyl, thiazolyl, thienyl, furyl, benzofuryl, benzothienyl, benzimidazolinyl, indolyl, indazolyl, and quinolinyl (in each of which optionally substituted) is selected from. However, when L is methylene and W is a 5- or 6-membered heterocyclic ring, R ³ is -Lx-NR ⁵ R ⁶ , -Lx-OR ⁷ , -Lx-S (O) _n R ⁸ , -Lx-C (O) R ⁹ , -S (O) _n -Lx-R ⁸ , -C (O) -Lx-R ⁹ , -Lx-CN, -Lx-NR ⁵ C (O) R ⁹ , -Lx-NR ⁵ S (O) _n R ⁸ , -Lx-NR ⁵ C (O) NR ¹⁰ R ¹¹ , -Lx-NR ⁵ S (O) _n NR ¹⁰ R ¹¹ , -Lx-NR ⁵ C (O) OR ⁷ , -Lx-NR ⁵ S (O) _n OR ⁷ , -NO ₂ , -Lx-C (O) NR ⁵ R ⁶ , -Lx-S (O) _n NR ⁵ R ⁶ , oxo ( = O)
R ⁴ is methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, and t-butyl, each of which is optionally substituted;
R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ and R ¹¹ are hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, and heterocycle (each of which, except for hydrogen, halo, -OH, -O (C ₁ ~C _{4 alkyl), - CN, C 1 ~C} 4 _{alkyl, -NH 2, -NH (C 1} ~C 4 _{alkyl), - N (C 1 ~C} 4 alkyl) ( C ₁ -C ₄ alkyl), - C (O) NH 2, -C (O) NH (C 1 ~C 4 alkyl), - C (O) N (C 1 ~C 4 alkyl) (C ₁ -C ₄ alkyl), - C (O) ( C 1 ~C 4 alkyl), - NHC (O) ( C 1 ~C 4 _{alkyl), - N (C 1 ~C} 4 _{alkyl) C (O) (C 1} ~ C _{4 alkyl), - S (O) n} NH 2, -S (O) n NH (C 1 ~C 4 _{alkyl), - S (O) n} n (C 1 ~C 4 alkyl) (C ₁ -C ₄ alkyl), -S (O) _n (C ₁ -C ₄ alkyl), -NHS (O) _n (C ₁ -C ₄ alkyl), -N (C ₁ -C ₄ alkyl) S (O) _n ( C ₁ -C ₄ alkyl), optionally C ₃ -C ₈ cycloalkyl are substituted, and heterocyclic (C ₁ -C ₄ alkyl 3-8 membered optionally substituted is Optionally substituted by one or more groups selected from: optionally substituted by, halo, -OH, -OMe, or -CN, or
Or R ⁵ and R ⁶ , R ⁵ and R ⁷ , R ⁵ and R ⁸ , R ⁵ and R ⁹ , and R ⁵ and R ¹⁰ together with the atoms to which they are attached form a ring It can be, the ring, _{halo, -OH, -O (C 1 ~C} 4 _{alkyl), - CN, C 1 ~C} 4 _{alkyl, -NH 2, -NH (C 1} ~C 4 alkyl), - N (C ₁ -C ₄ alkyl) (C ₁ ~C ₄ alkyl), - C (O) NH 2, -C (O) NH (C 1 ~C 4 alkyl), - C (O) N (C 1 ~ C ₄ alkyl) (C ₁ ~C ₄ alkyl), - C (O) ( C 1 ~C 4 alkyl), - NHC (O) ( C 1 ~C 4 _{alkyl), - N (C 1 ~C} 4 alkyl _{) C (O) (C 1} ~C 4 _{alkyl), - S (O) n} NH 2, -S (O) n NH (C 1 ~C 4 _{alkyl), - S (O) n} n (C 1 ~ C ₄ alkyl) (C ₁ ~C _{4 alkyl), - S (O) n} (C 1 ~C 4 _{alkyl), - NHS (O) n} (C 1 ~C 4 alkyl), - n (C ₁ ~C ₄ alkyl) S (O) _n (C ₁ -C ₄ alkyl), optionally substituted C ₃ -C ₈ cycloalkyl, and optionally substituted 3-8 membered heterocycle (C ₁ -C ₄ alkyl is halo, -OH Optionally substituted by one or more groups selected from: optionally substituted by-, --OMe, or --CN;
L _x is a bond or optionally substituted C ₁ -C ₄ alkylene.

In some embodiments, R ³ is hydrogen, -Lx-OR ⁷ , -Lx-S (O) _n R ⁸ , -Lx-C (O) R ⁹ , -S (O) _n -Lx-R ⁸ , -C (O) -Lx-R ⁹ , -Lx-NR ⁵ C (O) R ⁹ , -Lx-NR ⁵ S (O) _n R ⁸ , -Lx-NR ⁵ C (O) NR ¹⁰ R ¹¹ , -Lx-NR ⁵ S (O) _n NR ¹⁰ R ¹¹ , -Lx-C (O) NR ⁵ R ⁶ , -Lx-S (O) _n NR ⁵ R ⁶ , and oxo (= O) independent Selected,
R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ and R ¹¹ are hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, and heterocycle (each of which, except for hydrogen, halo, -OH, -O (C ₁ ~C _{4 alkyl), - CN, C 1 ~C} 4 _{alkyl, -NH 2, -NH (C 1} ~C 4 _{alkyl), - N (C 1 ~C} 4 alkyl) ( C ₁ -C ₄ alkyl), - C (O) NH 2, -C (O) NH (C 1 ~C 4 alkyl), - C (O) N (C 1 ~C 4 alkyl) (C ₁ -C ₄ alkyl), - C (O) ( C 1 ~C 4 alkyl), - NHC (O) ( C 1 ~C 4 _{alkyl), - N (C 1 ~C} 4 _{alkyl) C (O) (C 1} ~ C _{4 alkyl), - S (O) n} NH 2, -S (O) n NH (C 1 ~C 4 _{alkyl), - S (O) n} n (C 1 ~C 4 alkyl) (C ₁ -C ₄ alkyl), -S (O) _n (C ₁ -C ₄ alkyl), -NHS (O) _n (C ₁ -C ₄ alkyl), -N (C ₁ -C ₄ alkyl) S (O) _n ( C ₁ -C ₄ alkyl), optionally C ₃ -C ₈ cycloalkyl are substituted, and heterocyclic (C ₁ -C ₄ alkyl 3-8 membered optionally substituted is Optionally substituted by one or more groups selected from: optionally substituted by, halo, -OH, -OMe, or -CN, or
Or R ⁵ and R ⁶ , R ⁵ and R ⁷ , R ⁵ and R ⁸ , R ⁵ and R ⁹ , and R ⁵ and R ¹⁰ together with the atoms to which they are attached form a ring It can be, the ring, _{halo, -OH, -O (C 1 ~C} 4 _{alkyl), - CN, C 1 ~C} 4 _{alkyl, -NH 2, -NH (C 1} ~C 4 alkyl), - N (C ₁ -C ₄ alkyl) (C ₁ ~C ₄ alkyl), - C (O) NH 2, -C (O) NH (C 1 ~C 4 alkyl), - C (O) N (C 1 ~ C ₄ alkyl) (C ₁ ~C ₄ alkyl), - C (O) ( C 1 ~C 4 alkyl), - NHC (O) ( C 1 ~C 4 _{alkyl), - N (C 1 ~C} 4 alkyl _{) C (O) (C 1} ~C 4 _{alkyl), - S (O) n} NH 2, -S (O) n NH (C 1 ~C 4 _{alkyl), - S (O) n} n (C 1 ~ C ₄ alkyl) (C ₁ ~C _{4 alkyl), - S (O) n} (C 1 ~C 4 _{alkyl), - NHS (O) n} (C 1 ~C 4 alkyl), - n (C ₁ ~C ₄ alkyl) S (O) _n (C ₁ -C ₄ alkyl), optionally substituted C ₃ -C ₈ cycloalkyl, and optionally substituted 3-8 membered heterocycle (C ₁ -C ₄ alkyl is halo, -OH Optionally substituted by one or more groups selected from: optionally substituted by-, --OMe, or --CN;
L _x is a bond or optionally substituted C ₁ -C ₄ alkylene.

In some ^{embodiments, R 5, R 6, R} 7, R 8, R 9, R 10 and R ¹¹ are hydrogen, C ₁ -C ₄ alkyl, C ₃ -C ₈ cycloalkyl, C ₅ -C ₁₀ aryl, 5-10 membered heteroaryl, and 3-8 membered heterocyclic ring (each of which except for hydrogen, _{halo, -OH, -O (C 1 ~C} 4 alkyl), - CN, C ₁ -C _{4 alkyl, -NH 2, -NH (C 1} ~C 4 _{alkyl), - N (C 1 ~C} 4 alkyl) (C ₁ ~C ₄ alkyl), - C (O) NH 2, -C ( O) NH (C ₁ ~C ₄ alkyl), - C (O) N (C 1 ~C 4 alkyl) (C ₁ -C ₄ alkyl), - C (O) ( C 1 ~C 4 alkyl), - _{NHC (O) (C 1 ~C} 4 _{alkyl), - n (C 1 ~C} 4 _{alkyl) C (O) (C 1} ~C 4 _{alkyl), - S (O) n} NH 2, -S (O) _n NH (C ₁ ~C _{4 alkyl), - S (O) n} n (C 1 ~C 4 alkyl) (C ₁ -C _{4 alkyl), - S (O) n} (C 1 ~C 4 alkyl), _{-NHS (O) n (C 1} ~C 4 _{alkyl), - n (C 1 ~C} 4 _{alkyl) S (O) n (C} 1 ~C 4 alkyl), C ₃ is optionally substituted -C ₈ Cycloalkyl, and Heterocyclic 3-8 membered substituted by engagement (C ₁ -C ₄ alkyl, halo, -OH, -OMe, or optionally substituted by -CN) 1 or more groups selected from Optionally substituted).

In some embodiments, R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ and R ¹¹ are hydrogen, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl. , And t-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, phenyl, naphthyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, pyrazolyl, imidazolinyl, oxazolyl, isoxazolyl, thiazolyl, thienyl, furyl, benzofuryl , Benzothienyl, benzimidazolinyl, indolyl, indazolyl, quinolinyl, pyrrolidinyl, tetrahydrofuryl, tetrahydropyranyl, piperidinyl, piperazinyl, morpholinyl, homomorpholinyl, thiomorpholinyl, diazepanyl, and oxazepanyl (these S, with the exception of hydrogen, _{halo, -OH, -O (C 1 ~C} 4 alkyl), - CN, C ₁ -C _{4 alkyl, -NH 2, -NH (C 1} ~C 4 alkyl), - N (C ₁ ~C ₄ alkyl) (C ₁ ~C ₄ alkyl), - C (O) NH 2, -C (O) NH (C 1 ~C 4 alkyl), - C (O) N (C 1 -C ₄ alkyl) (C ₁ ~C ₄ alkyl), - C (O) ( C 1 ~C 4 alkyl), - NHC (O) ( C 1 ~C 4 _{alkyl), - N (C 1 ~C} 4 _{alkyl) C (O) (C 1} ~C 4 _{alkyl), - S (O) n} NH 2, -S (O) n NH (C 1 ~C 4 _{alkyl), - S (O) n} n (C 1 -C ₄ alkyl) (C ₁ ~C _{4 alkyl), - S (O) n} (C 1 ~C 4 _{alkyl), - NHS (O) n} (C 1 ~C 4 alkyl), - n (C ₁ ~ C _{4 alkyl) S (O) n (C} 1 ~C 4 alkyl), optionally C ₃ -C ₈ cycloalkyl are substituted, and 3-8 membered heterocyclic ring optionally substituted with (C ₁ ~ C ₄ alkyl, halo, -OH, -OMe, or from the case optionally substituted by one or more groups selected from being replaced) by) by -CN It stands to be selected.

In some embodiments, R ⁵ and R ⁶ , R ⁵ and R ⁷ , R ⁵ and R ⁸ , R ⁵ and R ⁹ , and R ⁵ and R ¹⁰ are taken together with the atoms to which they are attached. Te can form a ring, this ring is _{halo, -OH, -O (C 1 ~C} 4 _{alkyl), - CN, C 1 ~C} 4 _{alkyl, -NH 2, -NH (C 1} ~C _{4 alkyl), - N (C 1 ~C} 4 alkyl) (C ₁ -C ₄ alkyl), - C (O) NH 2, -C (O) NH (C 1 ~C 4 alkyl), - C (O ) N (C ₁ ~C ₄ alkyl) (C ₁ ~C ₄ alkyl), - C (O) ( C 1 ~C 4 alkyl), - NHC (O) ( C 1 ~C 4 alkyl), - N ( C ₁ -C _{4 alkyl) C (O) (C 1} ~C 4 _{alkyl), - S (O) n} NH 2, -S (O) n NH (C 1 ~C 4 alkyl), - S (O) _n n (C ₁ ~C ₄ alkyl) (C ₁ -C _{4 alkyl), - S (O) n} (C 1 ~C 4 _{alkyl), - NHS (O) n} (C 1 ~C 4 alkyl), - n (C ₁ ~C _{4 alkyl) S (O) n (C} 1 ~C 4 alkyl), the complex of the optionally 3-8 membered substituted by C ₃ -C ₈ cycloalkyl, and optionally substituted ring (C ₁ ~C ₄ Al The kill is optionally substituted with one or more groups selected from halo, —OH, —OMe, or —CN).

  In some embodiments, n is 2.

In some embodiments, L _x is a bond.

In some embodiments, L _x is optionally substituted C ₁ -C ₄ alkylene.

In some embodiments, the optionally substituted lower alkyl is —CF ₃ , —CF ₂ H, —CH ₂ NH ₂ , —CH ₂ CH ₂ NH ₂ , —CH ₂ OH, —CH ₂ CH _2. Selected from OH, —CH ₂ OCH ₃ , —CH ₂ CH ₂ OCH ₃ .

  Similarly, at least one compound selected from compounds 1-323 and / or at least one pharmaceutically acceptable salt thereof is provided.

  The compounds described herein, and / or pharmaceutically acceptable salts thereof, can be synthesized from commercially available starting materials by methods well known in the art in conjunction with the disclosure in this patent application. . The following scheme illustrates a method for preparing most of the compounds disclosed herein.

  As shown in Scheme I, compounds of formula (I) can be prepared by three routes.

Pathway A: A compound of formula (1) is converted to a compound of formula (2) in the presence of a base such as, but not limited to, K ₂ CO ₃ , Na ₂ CO ₃ , NaH, Et ₃ N or diisopropylethylamine (DIPEA). When reacted with a compound wherein m, R ¹ , L and W are as defined herein and X ¹ and X ² are halo selected from Cl, Br or I ), A compound of formula (3) can be obtained, and this compound of formula (3) is not limited to, but is limited to K ₂ CO ₃ , Na ₂ CO ₃ , Cs ₂ CO ₃ , NaH, t-BuONa, In the presence of a base such as t-BuOK, Et ₃ N or diisopropylethylamine (DIPEA), but not limited to, PdCl ₂ , Pd (OAc) ₂ , Pd ₂ (dba) ₃ , or Pd (PPh ₃ ) ₄ Palladium reagents such as, but not limited to, Ph ₃ P, t-Bu ₃ P, 2,2'-bis (diphenylphosphino) -1,1'-bisnaphthalene (BINAP), 1,1'- Bis (diphenylphosphino) ferrocene (dppf) or 1,3-bis (2,6-dichloride) chloride Ropirufeniru)-1H-imidazol-3-ium under catalysis with ligands, such as, the compound (of formula (4), R ² is as defined herein, M is When C ₁ -C selected from boronic acid / ester or tin is substituted by ₄ alkyl group) are reacted, to give a compound of formula (I).

Path B: but are not limited _{to, K 2 CO 3, Na 2} CO 3, NaH, in the presence of a base such as Et ₃ N or diisopropylethylamine (DIPEA), the compound of formula (1) wherein the (2) When reacted with a compound wherein m, R ¹ , L and W are as defined herein and X ¹ and X ² are halo selected from Cl, Br or I ), A compound of formula (3) can be obtained and this compound of formula (3) can be converted into HO- (R ³ ) _p or X ^3- (R ³ ) _p (where R ³ And p is as defined herein and X ³ is halo selected from Cl, Br or I) to give a compound of formula (4), This compound of formula (4) is not limited to K ₂ CO ₃ , Na ₂ CO ₃ , Cs ₂ CO ₃ , NaH, t-BuONa, t-BuOK, Et ₃ N or diisopropylethylamine (DIPEA) etc. PdCl ₂ , Pd (OAc) ₂ , Pd ₂ (dba) ₃ Or a palladium reagent such as Pd (PPh ₃ ) ₄ but not limited to: Ph ₃ P, t-Bu ₃ P, 2,2'-bis (diphenylphosphino) -1,1'-bisnaphthalene (BINAP ), 1,1'-bis (diphenylphosphino) ferrocene (dppf) or 1,3-bis (2,6-dipropylphenyl) -1H-imidazol-3-ium chloride and other ligands Below, a compound of formula (5) wherein R ² is as defined herein and M is a boronic acid / ester or tin substituted with a C ₁ -C ₄ alkyl group Selected) can give compounds of formula (I).

Path C: but are not limited _{to, K 2 CO 3, Na 2} CO 3, NaH, in the presence of a base such as Et ₃ N or diisopropylethylamine (DIPEA), the compound of formula (1) wherein the (2) When reacted with a compound wherein m, R ¹ , L and W are as defined herein and X ¹ and X ² are halo selected from Cl, Br or I ), A compound of formula (3) can be obtained, and this compound of formula (3) is not limited to, but is limited to K ₂ CO ₃ , Na ₂ CO ₃ , Cs ₂ CO ₃ , NaH, t-BuONa, In the presence of a base such as t-BuOK, Et ₃ N or diisopropylethylamine (DIPEA), but not limited to, PdCl ₂ , Pd (OAc) ₂ , Pd ₂ (dba) ₃ , or Pd (PPh ₃ ) ₄ etc. But not limited to: Ph ₃ P, t-Bu ₃ P, 2,2'-bis (diphenylphosphino) -1,1'-bisnaphthalene (BINAP), 1,1'-bis ( Diphenylphosphino) ferrocene (dppf) or 1,3-bis (2,6-diprochloride) When reacted with a compound of formula (5) under the action of a ligand such as ruphenyl) -1H-imidazol-3-ium, a compound of formula (4) can be obtained. After deprotection, the compound is reacted with HO- (R ³ ) _p or X ^3- (R ³ ) _p to give a compound of formula (I) wherein R ¹ , R ² , R ³ , L , W, m, p are as defined herein, X ¹ , X ² , X ³ are halo selected from Cl, Br or I, and M is C ₁ -C ₄ ) selected from boronic acid / esters or tins substituted by ₄ alkyl groups).

  The compounds thus obtained can be further modified at their peripheral positions to give the desired compounds. Synthetic chemistry transformations are described, for example, by R. Larock, Comprehensive Organic Transformations, VCH Publishers (1989), TW Greene and PGM Wuts, Protective Groups in Organic Synthesis, 3rd edition, John Wiley and Sons (1999), L. Fieser And M. Fieser, Fieser and Fieser's Reagents for Organic Synthesis, John Wiley and Sons (1994), and L. Paquette (ed), Encyclopedia of Reagents for Organic Synthesis, John Wiley and Sons (1995), and their sequels It is described in.

  Prior to use, at least one compound and / or at least one pharmaceutically acceptable salt described herein may be obtained by column chromatography, high performance liquid chromatography, crystallization, or other suitable method. Can be purified.

  Also provided is a composition comprising at least one compound and / or at least one pharmaceutically acceptable salt described herein, and at least one pharmaceutically acceptable carrier.

  Compositions comprising at least one compound and / or at least one pharmaceutically acceptable salt described herein are known variously, including oral, parenteral, by inhalation spray, or via an implanted reservoir. It can be administered by the method. The term “parenteral” as used herein is subcutaneous, intradermal, intravenous, intramuscular, intraarticular, intraarterial, intrasynovial, intrasternal, submeningeal, intralesional and intracranial. Injection or infusion techniques.

  Oral compositions can be any orally acceptable dosage form including, but not limited to, tablets, capsules, emulsions, and aqueous suspensions, dispersions, and solutions. it can. Commonly used carriers for tablets include lactose and corn starch. Lubricants such as magnesium stearate are also usually added to tablets. For oral administration in a capsule form, useful diluents include lactose and dried corn starch. When aqueous suspensions or emulsions are administered orally, the active ingredient can be suspended or dissolved in an oily phase combined with emulsifying or suspending agents. If desired, certain sweetening, flavoring, or coloring agents can be added.

  Sterile injectable compositions (e.g. aqueous or oily suspensions) are formulated according to techniques known in the art using suitable dispersing or wetting agents (e.g., Tween 80) and suspending agents. Can be The sterile injectable intermediate should be a sterile injectable solution or suspension in a nontoxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3-butanediol. You can also. Among the pharmaceutically acceptable vehicles and solvents that can be used are mannitol, water, Ringer's solution, and isotonic sodium chloride solution. In addition, sterile fixed oils are conventionally employed as a solvent or suspending medium (eg, synthetic mono- or diglycerides). Fatty acids such as oleic acid and its glyceride derivatives are useful in injectable intermediates, as well as natural pharmaceutically acceptable oils such as olive oil or castor oil, especially in their polyoxyethylated form. These oil solutions or suspensions can also contain a long-chain alcohol diluent or dispersant, or carboxymethyl cellulose or similar dispersing agents.

  Inhalable compositions can be prepared according to techniques well known in the field of pharmaceutical formulation and include benzyl alcohol or other suitable preservatives, absorption enhancers to enhance bioavailability, fluorocarbons, and / or It can be prepared as a solution in physiological saline using other solubilizers or dispersants known in the art.

  Topical compositions can be formulated in the form of oils, creams, lotions, ointments and the like. Suitable carriers for the composition include vegetable or mineral oil, white petrolatum (white soft paraffin), branched chain fat or oil, animal fat, and high molecular weight alcohol (greater than C12). In some embodiments, pharmaceutically acceptable carriers are those in which the active ingredient is soluble. Emulsifiers, stabilizers, humectants, and antioxidants, and agents that impart color or fragrance, if desired, may also be included. In addition, transdermal penetration enhancers can be used in their topical formulations. Examples of such accelerators can be found in US Pat. Nos. 3,989,816 and 4,444,762.

  Creams can be formulated from a mixture of mineral oil, self-emulsifying beeswax and water, in which the active ingredient dissolved in a small amount of oil such as almond oil is mixed. Examples of such creams are those containing about 40 parts water, about 20 parts beeswax, about 40 parts mineral oil and about 1 part almond oil. Ointments can be formulated by mixing a solution of the active ingredient in a vegetable oil, such as almond oil, with warm soft paraffin and cooling the mixture. An example of such an ointment is one containing about 30% by weight almond oil and about 70% by weight white soft paraffin.

  A pharmaceutically acceptable carrier is compatible with the active ingredient of the composition (and can stabilize the active ingredient in some embodiments) and is not deleterious to the subject to be treated. Refers to the carrier. For example, solubilizers such as cyclodextrins (which form certain, more soluble complexes with at least one compound and / or at least one pharmaceutically acceptable salt described herein) Can be utilized as pharmaceutical excipients for delivering active ingredients. Examples of other carriers include colloidal silicon dioxide, magnesium stearate, cellulose, sodium lauryl sulfate, and pigments such as D & C Yellow No. 10.

  Use an appropriate in vitro assay to pre-evaluate the efficacy of at least one compound and / or at least one pharmaceutically acceptable salt described herein in inhibiting the activity of Syk kinase can do. At least one compound and / or at least one pharmaceutically acceptable salt described herein can be further tested for efficacy in treating inflammatory diseases by in vivo assays. For example, a compound described herein, and / or a pharmaceutically acceptable salt thereof can be administered to an animal having an inflammatory disease (eg, a mouse model) to evaluate its therapeutic effect. be able to. Based on these results, an appropriate dosage range and route of administration for animals such as humans can also be determined.

  A method of inhibiting the activity of Syk kinase is also provided. This method comprises at least one kinase in an amount of at least one compound and / or at least one pharmaceutically acceptable salt described herein effective to inhibit the activity of Syk kinase. Contacting.

  At least one compound and / or at least one pharmaceutically acceptable salt described herein provides a beneficial therapeutic or prophylactic effect, eg, in a subject with an inflammatory disease or autoimmune disorder Can be used for. The term “inflammatory disease” or “inflammatory disorder” refers to a pathological condition that results in inflammation usually caused by neutrophil chemotaxis. Examples of such disorders include inflammatory skin diseases including psoriasis and atopic dermatitis, systemic scleroderma and sclerosis, responses associated with inflammatory bowel disease (IBD) (such as Crohn's disease and ulcerative colitis) Ischemic, including surgical tissue reperfusion injury, myocardial ischemic conditions such as myocardial infarction, cardiac arrest, reperfusion after cardiac surgery, and stenosis after percutaneous coronary angioplasty, stroke, and abdominal aortic aneurysm Reperfusion injury, brain edema secondary to stroke, skull trauma, hypotensive shock, asphyxia, adult respiratory distress syndrome, acute lung injury, Behcet's disease, dermatomyositis, multiple myositis, multiple sclerosis (MS), Autoimmune diseases such as dermatitis, meningitis, encephalitis, uveitis, osteoarthritis, lupus nephritis, rheumatoid arthritis (RA), Sjogren's syndrome, vasculitis, diseases involving leukocyte extravasation, central nervous system System (CNS) inflammatory disorder, sepsis or trauma Secondary organ damage syndrome, alcoholic hepatitis, bacterial pneumonia, antigen-antibody complex-mediated diseases including glomerulonephritis, sepsis, sarcoidosis, immunopathological response to tissue / organ transplant, pleurisy, alveoli Inflammation, vasculitis, pneumonia, chronic bronchitis, bronchiectasis, diffuse panbronchiolitis, irritable pneumonia, idiopathic pulmonary fibrosis (IPF) and pulmonary inflammation including cystic fibrosis are included. Preferred indications include, but are not limited to, chronic inflammation, autoimmune diabetes, rheumatoid arthritis (RA), rheumatoid spondylitis, gouty arthritis and other arthritic conditions, multiple sclerosis (MS), asthma, systemic Lupus lupus erythematosus, adult respiratory distress syndrome, Behcet's disease, psoriasis, chronic pulmonary inflammatory disease, graft versus host reaction, Crohn's disease, ulcerative colitis, inflammatory bowel disease (IBD), Alzheimer's disease, and inflammation and related Includes fever with a disease or disorder associated with the disorder.

  Use at least one compound and / or at least one pharmaceutically acceptable salt described herein to achieve a beneficial therapeutic or prophylactic effect, for example, in a subject with an autoimmune disease. Can do. The term “autoimmune disease” refers to a disease or disorder resulting from and / or directed to an individual's own tissue or organ, or a co-segregation or occurrence thereof, or a condition resulting therefrom. Examples of autoimmune diseases include, but are not limited to, lupus, myasthenia gravis, multiple sclerosis (MS), rheumatoid arthritis (RA), psoriasis, inflammatory bowel disease, asthma and idiopathic thrombocytopenic purpura Disease and myeloproliferative disorders such as myelofibrosis, PV / ET (erythrocytosis / essential postthrombocythemia myelofibrosis).

  In some embodiments, at least one compound and / or at least one pharmaceutically acceptable salt described herein is administered in conjunction with another therapeutic agent. In some embodiments, the other therapeutic agent is one that is normally administered to a patient having the disease or condition being treated. For example, the other therapeutic agent may be an anti-inflammatory or anti-neoplastic agent depending on the disease or condition being treated. At least one compound and / or at least one pharmaceutically acceptable salt described herein can be administered with other therapeutic agents in a single dosage form or as separate dosage forms. . When administered as a separate dosage form, the other therapeutic agent may be prior to, concurrent with, or after administration of at least one compound and / or at least one pharmaceutically acceptable salt described herein. Can be administered.

  In some embodiments, at least one compound and / or at least one pharmaceutically acceptable salt described herein is administered in conjunction with an anti-inflammatory agent. Non-limiting examples of anti-inflammatory agents include corticosteroids (e.g. fluticasone propionate, beclomethasone dipropionate, mometasone furoate, triamcinolone acetonide or budesonide), disease modifiers (e.g. antimalarial drugs, methotrexate, sulfasalazine, Mesalamine, azathioprine, 6-mercaptopurine, metronidazole, injectable gold and gold for oral use, or D-penicillamine), non-steroidal anti-inflammatory drugs (e.g. acetominophen, aspirin, sodium salicylate, sodium cromoglycate , Magnesium salicylate, magnesium choline salicylate, salicylsalicylic acid, ibuprofen, naproxen, diclofenac, diflunisal, etodolac, fenoprofen calcium, fluriprofen, pyroxyl , Indomethacin, ketoprofen, ketorolac tromethamine, meclofenamate, sodium meclofenamate, mefenamic acid, nabumetone, oxaprozin, phenylbutylnitrone (PBN), sulindac, or tolmethine), COX-2 inhibitor, inhibition of cytokine synthesis / release Agents (eg, anti-cytokine antibodies, anti-cytokine receptor antibodies, etc.) are included.

  The following examples are intended to be purely exemplary and should in no way be considered limiting. Efforts have been made to ensure accuracy with respect to numbers used (eg amounts, temperature, etc.) but some experimental errors and deviations should be accounted for. Unless indicated otherwise, parts are parts by weight, temperature is in degrees Centigrade, and pressure is at or near atmospheric. All MS data was verified by Agilent 6120 and / or Agilent 1100. Except for the intermediates, all reagents used in the present invention are commercially available. All compound names except reagents were generated by Chemdraw 12.0.

In the examples below, the following abbreviations are used.
Boc tert-butoxycarbonyl
Boc ₂ O di-t-butyl-dicarbonate
CDI N, N'-Carbonyldiimidazole
DAST diethylaminosulfur trifluoride
DCM dichloromethane
DMF N, N-dimethylformamide
DMAP 4-Dimethylaminopyridine
DIPEA N, N-Diisopropylethylamine
EDCI 1- (3-Dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride
EtOAc / EA ethyl acetate
Et ₃ N triethylamine
HATU O- (7-azabenzotriazol-1-yl) -N, N, N ', N'-tetra-methyluronium hexafluorophosphate
HOAc acetic acid
HOBt hydroxybenzotriazole
mL milliliter
mg milligrams
min minutes
MeOH methanol
MsCl Methanesulfonyl chloride
NaH sodium hydride
PE petroleum ether
Pd (dppf) Cl ₂ 1,1'-bis (diphenylphosphino) ferrocene-palladium (II) dichloride
Pd ₂ (dba) ₃ Tris (dibenzylideneacetone) dipalladium (0)
Pd (PPh ₃ ) ₄ tetrakis (triphenylphosphine) palladium (0)
PPh ₃ Triphenylphosphine
TBDMSCl tert-butyldimethylsilyl chloride
TMSNCO Trimethylsilyl isocyanate
THF tetrahydrofuran

Intermediate 1
2-Methyl-4- (4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl) morpholine

(A) 4- (2-Methylmorpholino) aniline
To a mixture of 1-fluoro-4-nitrobenzene (5.64 g, 40 mmol) and K ₂ CO ₃ (11.1 g, 80 mmol) in DMSO (30 mL) was added 2-methylmorpholine (4.05 g, 40 mmol), then Heated at 100 ° C. for 4 hours. The solution was poured into water (300 mL) and extracted with EA (3 × 100 mL). The combined organic phases were washed with brine, dried and filtered, and Pd / C (1 g) was added to the filtrate. H ₂ was introduced and the solution was stirred at room temperature overnight. The catalyst was filtered and the filtrate was concentrated to give the product as a light red solid. MS (m / z): 223 (M + H) ^<+> .

(B) 4- (4-Bromophenyl) -2-methylmorpholine
To a solution of 4- (2-methylmorpholino) aniline (7.21 g, 37.5 mmol) in 100 mL of 40% HBr solution at −10 to 0 ° C., NaNO ₂ (2.59 g, 37.5 mmol) H ₂ O (15 mL) The solution was added. The mixture was stirred for 30 minutes and added dropwise to a solution of CuBr (2.96 g, 20.6 mmol) in 40% HBr solution (30 mL). The resulting mixture was stirred and heated at 60 ° C. for 2 hours. Next, the reaction solution was adjusted to pH> 7 with 2N NaOH solution and extracted with EA. The combined organic phases were washed with brine, dried and concentrated to give the crude product as a black oil. MS (m / z): 256 (M + H) ^<+> .

(C) 2-methyl-4- (4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl) morpholine
4- (4-Bromophenyl) -2-methylmorpholine (8 g, about 31 mmol), 4,4,4 ′, 4 ′, 5,5,5 ′, 5′-octamethyl-2 in DMSO (80 mL), Mixture of 2′-bi (1,2-dioxaborolane) (10.3 g, 40.6 mmol), KOAc (4.6 g, 46.5 mmol), and PdCl ₂ (dppf) (2.26 g, 3.1 mmol) under N ₂ at 70 ° C. For 4 hours. The reaction mixture was partitioned between EA and water. The combined organic phases were dried, concentrated and purified on silica gel chromatography eluting with EA / PE = 5: 1 to give the product as a light yellow solid. MS (m / z): 304 (M + H) ^<+> .

Intermediate 2
(2S, 6R) -2,6-Dimethyl-4- (4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl) morpholine

The title compound was prepared according to the procedure of Intermediate 1 using 1-fluoro-4-nitrobenzene and (2S, 6R) -2,6-dimethylmorpholine instead. MS (m / z): 318 (M + H) ^<+> .

Intermediate 3
4,4-difluoro-1- (4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl) piperidine

The title compound was prepared according to the procedure of Intermediate 1 using 1-fluoro-4-nitrobenzene and 4,4-difluoropiperidine instead. MS (m / z): 324 (M + H) ^<+> .

Intermediate 4
1- (4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl) piperidine

The title compound was prepared according to the procedure of Intermediate 1 using 1-fluoro-4-nitrobenzene and piperidine instead. MS (m / z): 288 (M + H) ^<+> .

Intermediate 5
2- (1- (4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl) piperidin-4-yl) propan-2-ol

The title compound was prepared according to the procedure of Intermediate 1 using 1-fluoro-4-nitrobenzene and 2- (piperidin-4-yl) propan-2-ol instead. MS (m / z): 346 (M + H) ^<+> .

Intermediate 6
4-Methoxy-1- (4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl) piperidine

The title compound was prepared according to the procedure of Intermediate 1 using 1-fluoro-4-nitrobenzene and 4-methoxypiperidine instead. MS (m / z): 318 (M + H) ^<+> .

Intermediate 7
1- (methylsulfonyl) -4- (4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl) piperazine

To a solution of 1- (4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl) piperazine hydrochloride (1.62 g, 5 mmol) in CH ₂ Cl ₂ (60 mL) Et ₃ N (1.67 mL, 12 mmol) and MsCl (465 uL, 6 mmol) were added at 0 ° C. The reaction was stirred at 0 ° C. for 1 hour. The reaction was then washed with aqueous NaHCO ₃ (15 mL), H ₂ O (15 mL), and brine (15 mL), dried over Na ₂ SO ₄ , concentrated and silica gel column chromatography (EA: PE = 1: 1) gave a yellow oil. MS (m / z): 367 (M + H) ^<+> .

Intermediate 8
1- (Ethylsulfonyl) -4- (4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl) piperazine

The title compound was prepared according to the procedure of Intermediate 7 using EtSO ₂ Cl instead. MS (m / z): 381 (M + H) ^<+> .

Intermediate 9
4,4,5,5-tetramethyl-2- (4- (tetrahydro-2H-pyran-4-yl) phenyl) -1,3,2-dioxaborolane

(A) 4- (4-Bromophenyl) -tetrahydro-2H-pyran
A solution of 4- (tetrahydro-2H-pyran-4-yl) benzenamine (1.79 g, 10.10 mmol) in HBr (15 mL) and water (5 mL) was stirred at 0 ° C. for 10 minutes, and then the mixture was added to the mixture. At −5 ° C. to 0 ° C., NaNO ₂ (0.77 g) was added. The mixture was stirred at -5 ° C for 30 minutes. To this mixture was then added a solution of CuBr in HBr (3 mL), after which the mixture was heated at 100 ° C. for 2 hours. The mixture was cooled to room temperature, partitioned between 2N NaOH and EA, washed with water and aqueous NaCl, and dried over Na ₂ SO ₄ . Volatiles were removed in vacuo and the residue was purified by silica gel column chromatography using PE / EA (10: 1-4: 1) to give 1.11 g of the title compound.

(B) 4,4,5,5-Tetramethyl-2- (4- (tetrahydro-2H-pyran-4-yl) phenyl) -1,3,2-dioxaborolane
To a solution of 4- (4-bromophenyl) tetrahydro-2H-pyran (241 mg, 1 mmol) in dioxane (15 mL), KOAc (294 mg, 3 mmol), PdCl ₂ (dppf) (110 mg, 0.15 mmol), and 4,4, 4 ′, 4 ′, 5,5,5 ′, 5′-octamethyl-2,2′-bi (1,3,2-dioxaborolane) (381 mg, 1.5 mmol) was added. The mixture was stirred at 80 ° C. overnight. The reaction was filtered and concentrated to give the crude product, which was used directly for the next step. MS (m / z): 289 (M + H) ^<+> .

Intermediate 10
5- (Hydroxymethyl) piperidin-2-one

(A) ethyl 6-oxopiperidine-3-carboxylate
To a solution of 6-oxopiperidine-3-carboxylic acid (1.72 g, 12.3 mmol) in EtOH (50 mL) was added dropwise SOCl ₂ (2.93 g, 24.6 mmol) at 0 ° C. The reaction was then stirred at room temperature for 24 hours. The reaction mixture was concentrated and the residue was triturated with ether to give a white solid. MS (m / z): 172 (M + H) ^<+> .

(B) 5- (hydroxymethyl) piperidin-2-one
Under N ₂ , 1.2N DIBAL H (2.5 mL, 3 mmol) was added dropwise to a solution of ethyl 6-oxopiperidine-3-carboxylate (171 mg, 1 mmol) in THF (5 mL) at −70 ° C. The mixture was stirred at 25 ° C. for 1 hour. The reaction was decomposed by the dropwise addition of MeOH (120 uL), 30% K ₂ CO ₃ (1.2 mL) in toluene (1 mL). The mixture was filtered and the granular precipitate was washed with ethanol (5 mL). The filtrate was evaporated to give a yellow oil. This oil was used directly for the next step. MS (m / z): 130 (M + H) ^<+> .

Intermediate 11
2- (4- (4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl) piperazin-1-yl) ethanol

To a solution of 1- (4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl) piperazine hydrochloride (1.62 g, 5 mmol) in DMF (50 mL) was added K ₂ CO ₃ (2.07 g, 15 mmol) and 2-bromoethanol (937.5 mg, 7.5 mmol) were added. The mixture was stirred at 80 ° C. for 5 hours, then poured into water (30 mL) and extracted with EA (20 mL × 3), the organic phase washed with water, brine and concentrated to give a brown solid. It was. MS (m / z): 333 (M + H) ^<+> .

Intermediate 12
1- (Tetrahydro-2H-pyran-4-yl) -4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1H-pyrazole

(A) Tetrahydro-2H-pyran-4-ylmethanesulfonate Tetrahydro-2H-pyran-4-ol (612 mg, 6 mmol) in DCM (5 mL) at room temperature with Et ₃ N (1002 uL, 7.2 mmol) and MsCl ( 510 uL, 6.6 mmol) was added. The mixture was stirred at room temperature for 2 hours. The mixture was then concentrated to give a white solid that was used directly for the next step.

(B) 4-Bromo-1- (tetrahydro-2H-pyran-4-yl) -1H-pyrazole
To a solution of 4-bromo-1H-pyrazole (588 mg, 4 mmol) in DMF (15 mL) was added Cs ₂ CO ₃ (1.95 g, 6 mmol) and tetrahydro-2H-pyran-4-ylmethanesulfonate (6 mmol) at room temperature. . The mixture was stirred at 120 ° C. for 18 hours. The mixture was then dissolved in EA (50 mL), washed with H ₂ O (25 mL) and brine (25 mL), dried over Na ₂ SO ₄ and concentrated, silica gel column chromatography (EA: PE = 1: Purification by 5) gave a white solid. MS (m / z): 233 (M + H) ^<+> .

(C) 1- (Tetrahydro-2H-pyran-4-yl) -4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1H-pyrazole
To a solution of 4-bromo-1- (tetrahydro-2H-pyran-4-yl) -1H-pyrazole (745 mg, 3.21 mmol) in dioxane (15 mL), KOAc (944 mg, 9.63 mmol), PdCl ₂ (dppf) (352 mg 0.48 mmol), and 4,4,4 ′, 4 ′, 5,5,5 ′, 5′-octamethyl-2,2′-bi (1,3,2-dioxaborolane) (1.22 g, 4.82 mmol) Was added. The mixture was stirred at 80 ° C. for 24 hours, then filtered and concentrated to give the crude product, which was used directly for the next step. MS (m / z): 279 (M + H) ^<+> .

Intermediate 13
1- (4- (4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl) piperidin-1-yl) ethanone

(A) 1- (4- (4-Bromophenyl) piperidin-1-yl) ethanone
To a solution of 4- (4-bromophenyl) piperidine hydrochloride (500 mg, 1.81 mmol) in anhydrous THF was added TEA (366 mg, 3.62 mmol). The solution was cooled to 0 ° C. and acetyl chloride (170 mg, 2.17 mmol) was added dropwise and stirred at room temperature overnight. The solvent was concentrated in vacuo, water was added and extracted with EA. The organic phase was washed with aqueous 2N NaOH, brine, then dried over anhydrous Na ₂ SO ₄ and concentrated to give the title compound, which was used directly in the next step.

(B) 1- (4- (4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl) piperidin-1-yl) ethanone
1- (4- (4-Bromophenyl) piperidin-1-yl) ethanone (620 mg, 2.2 mmol), 4,4,5,5-tetramethyl-2- (4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl) -1,3,2-dioxaborolane (667 mg, 2.6 mmol), Cs ₂ CO ₃ (1.43 g, 4.4 mmol) and Pd (dppf) Cl ₂ (60 mg) in a flask Dissolved in dioxane. N ₂ was introduced into the mixture and stirred at 50 ° C. for 5 hours. The solvent was then removed in vacuo and the residue was purified by flash column chromatography (PE: EA = 0: 100 to 3:10) to give the title product. MS (m / z): 330 (M + H) ^<+> .

Intermediate 14
1- (4- (4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl) piperazin-1-yl) ethanone

The title compound was prepared according to the procedure for Intermediate 7 using MeCOCl instead. MS (m / z): 331 (M + H) ^<+> .

Intermediate 15
N, N-2-trimethyl-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) aniline

(A) 4-Bromo-N, N-2-trimethylaniline
To a solution of 4-bromo-2-methylaniline (558 mg, 3 mmol) in DMF (10 mL) was added K ₂ CO ₃ (1242 mg, 9 mmol) and iodomethane (1278 mg, 9 mmol). The mixture was stirred at 100 ° C. for 24 hours. TLC and LC-MS indicated that the reaction was complete. The reaction solution was poured into H ₂ O (20 mL) and extracted with EA, the organic phase was washed with water and brine and concentrated to give the product as a light yellow oil. MS (m / z): 216 (M + H) ^<+> .

(B) N, N-2-trimethyl-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) aniline
To a solution of 4-bromo-N, N-2-trimethylaniline (571.7 mg, 2.67 mmol) in DMSO (20 mL), KOAc (787 mg, 8.01 mmol), PdCl ₂ (dppf) (293 mg, 0.4 mmol), and 4, 4,4 ′, 4 ′, 5,5,5 ′, 5′-octamethyl-2,2′-bi (1,3,2-dioxaborolane) (1.36 g, 5.34 mmol) was added. The mixture was stirred at 80 ° C. for 6 hours under N ₂ . The reaction was added to water (150 mL) and extracted with EA, the organic phase was washed with brine and concentrated to give the crude. The crude product was purified by preparative TLC (EA: PE = 1: 5) to give a white solid. MS (m / z): 262 (M + H) ^<+> .

Intermediate 16
2-Chloro-N, N-dimethyl-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) aniline

The title compound was prepared according to the procedure for intermediate 15 (A). MS (m / z): 282 (M + H) ^<+> .

Intermediate 17
1-Methyl-5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1H-indazole

The title compound was prepared according to the procedure for intermediate 15 (A). MS (m / z): 259 (M + H) ^<+> .

Intermediate 18
1-Methyl-6- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1H-indole

The title compound was prepared according to the procedure for intermediate 15 (A). MS (m / z): 258 (M + H) ^<+> .

Intermediate 19
N- (2-methoxyethyl) -4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) aniline

(A) 4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) aniline
4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenylcarbamate tert-butyl (300 mg, 0.94 mmol) was dissolved in HCl / EA solution at 20 ° C. Stir for 4 hours. The reaction was concentrated to give a white solid that was used directly for the next step.

(B) N- (2-methoxyethyl) -4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) aniline
To a solution of 4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) aniline (0.94 mmol) in DMF (10 mL), K ₂ CO ₃ (270 mg, 1.5 mmol) and 1-Bromo-2-methoxyethane (209 mg, 1.5 mmol) was added and the mixture was then stirred at 100 ° C. for 24 hours. The solution was quenched with water and extracted with EA, the organic phase was washed with water and brine, concentrated and purified by preparative TLC (EA: PE = 1: 5) to give a white solid. MS (m / z): 278 (M + H) ^<+> .

Intermediate 20
2- (2-Methoxy-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenoxy) -N, N-dimethylethanamine

The title compound was prepared according to the procedure for intermediate 19 (B). MS (m / z): 322 (M + H) ^<+> .

Intermediate 21
N-methyl-2- (4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenoxy) acetamide

The title compound was prepared according to the procedure for intermediate 19 (B). MS (m / z): 292 (M + H) ^<+> .

Intermediate 22
N-methyl-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) aniline

The title compound was prepared according to the procedure for Intermediate 1 (A) and 15 (A). MS (m / z): 234 (M + H) ^<+> .

Intermediate 23
1- (4- (2-Methyl-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl) piperazin-1-yl) ethanone

The title compound was prepared according to the procedure for Intermediate 13. MS (m / z): 345 (M + H) ^<+> .

Intermediate 24
1- (2-Methyl-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl) -4- (methylsulfonyl) piperazine

The title compound was prepared according to the procedure for Intermediate 13. MS (m / z): 381 (M + H) ^<+> .

Intermediate 25
4- (4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) benzyl) morpholine

(A) 4- (4-Bromobenzyl) morpholine
1-Bromo-4- (bromomethyl) benzene (2 g, 8 mmol) and morpholine (2.1 g, 24 mmol) are dissolved in anhydrous DMF, K ₂ CO ₃ (5.53 g, 40 mmol) is added, and the mixture is stirred at 50 ° C. Stir overnight. This was poured into water and extracted with EA / H ₂ O, the organic phase was washed with brine, dried over anhydrous Na ₂ SO ₄ and concentrated to give the title product as a colorless oil (100% yield).

(B) 4- (4- (4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl) benzyl) morpholine Reactant 4- (4-bromobenzyl) morpholine (500 mg, 2 mmol), 4,4,5,5-tetramethyl-2- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1,3,2-dioxaborolane (610 mg 2.4 mmol), KOAc (294 mg, 3 mmol), and Pd (dppf) Cl ₂ (50 mg), dioxane were mixed in a cube. The cubic container was sealed and allowed to react overnight at 80 ° C. under N ₂ atmosphere. The mixture was then purified by flash column chromatography (MeOH / H ₂ O) to give the title product as a yellow solid (52% yield). MS (m / z): 304 (M + H) ^<+> .

Intermediate 26
N-methyl-N- (4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) benzyl) acetamide

反応剤の2-(4-(ブロモメチル)フェニル)-4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン(400mg、1.34mmol)を、MeNH₂のMeOH溶液(5N、5mmol)に溶解した。この混合物を40℃で4時間撹拌し、次に溶媒を真空(vacum)中で除去し、残さをDCMに溶解して、氷浴を用いて0℃に冷却した。次に、TEA(404mg、4mmol)を加え、AcCl(160mg、2mmol)を滴下して加えた。その後、氷浴を取り去り、この混合物を室温で30分間撹拌し、次に、EA及びH₂Oにより分配した。有機相をブラインにより洗浄し、無水Na₂SO₄で脱水して濃縮すると、表題生成物が、白色固体(77%収率)として得られた。MS(m/z):290(M+H)⁺。

Reactant 2- (4- (bromomethyl) phenyl) -4,4,5,5-tetramethyl-1,3,2-dioxaborolane (400 mg, 1.34 mmol) was added to MeNH ₂ in MeOH (5N, 5 mmol). Dissolved in. The mixture was stirred at 40 ° C. for 4 hours, then the solvent was removed in vacuo, the residue was dissolved in DCM and cooled to 0 ° C. using an ice bath. Next, TEA (404 mg, 4 mmol) was added and AcCl (160 mg, 2 mmol) was added dropwise. The ice bath was then removed and the mixture was stirred at room temperature for 30 minutes and then partitioned between EA and H ₂ O. The organic phase was washed with brine, dried over anhydrous Na ₂ SO ₄ and concentrated to give the title product as a white solid (77% yield). MS (m / z): 290 (M + H) ^<+> .

Intermediate 27
2- (4- (4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl) piperidin-1-yl) ethanol

The title compound was prepared according to the procedure for Intermediate 11. MS (m / z): 332 (M + H) ^<+> .

Intermediate 28
N, N-dimethyl-2- (4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl) ethanamine

(A) 4-Bromophenethyl methanesulfonate
2- (4-Bromophenyl) ethanol (2 g, 10 mmol) and TEA (1.515 g, 15 mmol) were dissolved in DCM and the mixture was cooled using an ice bath. Then MsCl (1.375 g, 12 mmol) was added slowly. The mixture was then stirred for 2 hours, then poured into water and extracted with DCM. The organic phase was concentrated to give the title product as a colorless oil (97% yield).

(B) 2- (4-Bromophenyl) -N, N-dimethylethanamine Dissolve 4-bromophenethyl methanesulfonate (1 g, 3.58 mmol) and dimethylamine hydrochloride (880 mg, 10.74 mmol) in DMF. , K ₂ CO ₃ (1.5 g, 10.74 mmol) was added and the mixture was stirred at 50 ° C. overnight. This was then poured into water and extracted with EA. The organic phase was washed with brine, dried over anhydrous Na ₂ SO ₄ and concentrated to give the title product as a brown solid (95% yield).

(C) N, N-dimethyl-2- (4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl) ethanamine 2- (4-bromo Phenyl) -N, N-dimethylethanamine (500 mg, 2.2 mmol), 4,4,5,5-tetramethyl-2- (4,4,5,5-tetramethyl-1,3,2-dioxaborolane- 2-yl) -1,3,2-dioxaborolane (660 mg, 2.6 mmol), KOAc (324 mg, 3.3 mmol), and Pd (dppf) Cl ₂ (50 mg), dioxane were mixed in a cubic container. The cubic container was sealed and allowed to react overnight at 80 ° C. under N ₂ atmosphere. This was cooled and purified by flash column chromatography (MeOH / H ₂ O) to give the title product as a white solid (69% yield).
¹ H NMR (400MHz, CDCl ₃ ) δ 7.75 (d, 2H), 7.22 (d, J = 8.1 Hz, 2H), 3.16-3.12 (m, 4H), 2.74 (s, 6H), 1.33 (s, 12H )

Intermediate 29
2-Methyl-1- (4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl) propan-2-ol

(A) 1- (4-Bromophenyl) -2-methylpropan-2-ol N ₂ was introduced into a mixture of ethyl 2- (4-bromophenyl) acetate (2.5 g, 10 mmol) in anhydrous THF, 0 Cooled to ° C. Next, methylmagnesium bromide (2M, 6 mL, 12 mmol) was added dropwise while maintaining the temperature between 0-5 ° C. The mixture was then stirred at 0 ° C. for 2 hours. Next, a few drops of water were added. After a while, the mixture was poured into water and extracted with EA. The organic phase was washed with brine, dried over anhydrous Na ₂ SO ₄ and concentrated to give the title product as a colorless oil (100% yield).

(B) 2-Methyl-1- (4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl) propan-2-ol
1- (4-Bromophenyl) -2-methylpropan-2-ol (500 mg, 2.2 mmol), 4,4,5,5-tetramethyl-2- (4,4,5,5-tetramethyl-1 , 3,2-dioxaborolan-2-yl) -1,3,2-dioxaborolane (660 mg, 2.6 mmol), KOAc (324 mg, 3.3 mmol), and Pd (dppf) Cl ₂ , dioxane were mixed in a cubic container. . The cubic container was sealed and reacted overnight at 80 ° C. under N ₂ atmosphere. The mixture is cooled and then partitioned with EA / H ₂ O, the organic phase is washed with brine, dried over anhydrous Na ₂ SO ₄ and concentrated to give the title compound as a black solid that can be further purified. Not used for next step.

Intermediate 30
1- (4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl) cyclopropanecarbonitrile

  The title compound was prepared according to the procedure for intermediate 15 (B).

Intermediate 31
1- (4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl) cyclobutanecarbonitrile

  The title compound was prepared according to the procedure for intermediate 15 (B).

Intermediate 32
2-Methyl-2- (4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl) propan-1-ol

(A) Ethyl 2- (4-bromophenyl) -2-methylpropanoate A mixture of ethyl 2- (4-bromophenyl) acetate (2.5 g, 10 mmol) in anhydrous THF was cooled to 0 ° C., then the temperature NaH (720 mg, 15 mmol) was added in small portions while maintaining between 0-5 ° C. The mixture was then stirred at room temperature for 2 hours and then cooled to 0 ° C. MeI (2.13 g, 15 mmol) was added and the mixture was stirred at room temperature overnight. Next, a few drops of water were added. After a while, the mixture was poured into water and extracted with EA, the organic phase was washed with brine, dried over anhydrous Na ₂ SO ₄ and concentrated to give the title product as a colorless oil (98% yield). ) Was obtained.

(B) 2- (4-Bromophenyl) -2-methylpropan-1-ol A mixture of LiAlH ₄ (456 mg, 12 mmol) in anhydrous THF was added to anhydrous THF while maintaining the temperature between 0-5 ° C. In ethyl 2- (4-bromophenyl) -2-methylpropanoate (2.75 g, 10 mmol) was added dropwise. The mixture was stirred at 0 ° C. for 2 hours. Then water (456 mg), 2N HCl (456 mg), and water (456 mg) were added sequentially. The mixture was filtered to remove the precipitate. The filtrate was concentrated to give the title product as a colorless oil (89% yield).

(C) 2-Methyl-2- (4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl) propan-1-ol
2- (4-Bromophenyl) -2-methylpropan-1-ol (500 mg, 2 mmol), 4,4,5,5-tetramethyl-2- (4,4,5,5-tetramethyl-1, 3,2-dioxaborolan-2-yl) -1,3,2-dioxaborolane (610 mg, 2.4 mmol), KOAc (300 mg, 3.0 mmol), and Pd (dppf) Cl ₂ (50 mg), dioxane in a cubic container Mixed. The cubic container was sealed and allowed to react overnight at 80 ° C. under N ₂ atmosphere. The mixture is cooled and then partitioned with EA / H ₂ O and the organic phase is washed with brine, dried over anhydrous Na ₂ SO ₄ and concentrated to give the title product as a black solid that is further purified. Without being used for the next step.

Intermediate 33
1- (methylsulfonyl) -4- (4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl) piperidine

The title compound was prepared according to the procedure for Intermediate 13. MS (m / z): 366 (M + H) ^<+> .

Intermediates 34 and 35
(S) -tert-butyl 2-((R) -1-((7-chloropyrido [3,4-b] pyrazin-5-yl) oxy) ethyl) morpholine-4-carboxylate and (S) -tert -Butyl 2-((S) -1-((7-chloropyrido [3,4-b] pyrazin-5-yl) oxy) ethyl) morpholine-4-carboxylate

(A) (S) -tert-butyl 2- (methoxy (methyl) carbamoyl) morpholine-4-carboxylate
In DCM (100 mL), (S) -4- (tert-butoxycarbonyl) morpholine-2-carboxylic acid (6.93 g, 30 mmol), DIPEA (9.70 g, 75 mmol), and N, O-dimethylhydroxylamine HCl (4.39 g, 45 mmol) was treated with HATU (22.8 g, 60 mmol) at room temperature. The reaction mixture was stirred for 16 hours, then poured into saturated aqueous sodium bicarbonate and extracted with CH ₂ Cl ₂ . The combined extracts were dried over MgSO ₄ , filtered and concentrated to give 14.95 g of a light yellow oil. MS (m / z): 175 (M + H-Boc) ^<+> .

(B) (S) -tert-butyl 2-acetylmorpholine-4-carboxylate (S) -tert-butyl 2- (methoxy (methyl) carbamoyl) morpholine-4-carboxylate obtained above was replaced with nitrogen. Under room temperature, dissolved in THF (60 mL), then the mixture was cooled to 0 ° C. Methyl magnesium bromide (3M solution in diethyl ether, 30 mL, 90 mmol) was added in small portions. The reaction mixture was stirred at 0 ° C. for 1 hour, warmed to room temperature and stirred for 16 hours. The mixture was again cooled to 0 ° C. and saturated aqueous ammonium chloride was added slowly. The mixture was extracted with EtOAc and the organic phase was washed with brine, dried over MgSO ₄ , filtered and concentrated and purified by silica gel chromatography (petroleum ether: ethyl acetate = 5: 1) to give a colorless oil. 2.4g was obtained. MS (m / z): 130 (M + H-Boc) ^<+> .
¹ H NMR (400 MHz, cdcl3) δ 4.20-4.08 (m, 1H), 3.98-3.93 (m, 1H), 3.89-3.78 (m, 2H), 3.59-3.52 (m, 1H), 2.99-2.91 ( m, 1H), 2.84-2.76 (m, 1H), 2.22 (s, 3H), 1.46 (d, J = 0.7, 9H).

(C) (S) -tert-butyl 2-((R) -1-((7-chloropyrido [3,4-b] pyrazin-5-yl) oxy) ethyl) morpholine-4-carboxylate and (S ) -tert-butyl 2-((S) -1-((7-chloropyrido [3,4-b] pyrazin-5-yl) oxy) ethyl) morpholine-4-carboxylate (S To) -tert-butyl 2-acetylmorpholine-4-carboxylate (2.4 g, 10.5 mmol) at 0 ° C. was added sodium borohydride (0.59 g, 15.7 mmol). After 2 hours, the reaction was quenched with saturated ammonium chloride solution and extracted with dichloromethane. The organic phase was dried over magnesium sulfate, filtered and concentrated. The residue was dissolved in N, N-dimethylformamide (50 mL) and the mixture was cooled to 5 ° C. under a nitrogen atmosphere. Sodium hydride (60% in mineral oil, 0.55 g, 13.6 mmol) was added in portions over 15 minutes and the mixture was stirred at 5 ° C. for 1 hour. Next, 5,7-dichloropyrido [3,4-b] pyrazine (2.10 g, 10.5 mmol) was added in portions and the mixture was stirred at 5 ° C. for an additional hour and saturated aqueous ammonium chloride (50 mL) was added. To quench. The solution was partitioned between ethyl acetate and water. The aqueous liquid was re-extracted with ethyl acetate and the combined organic phases were washed with water, separated using a layer separation cartridge and concentrated to give a brown oil. The crude residue was dissolved in DCM and purified by silica gel column chromatography eluting with a 12-62% ethyl acetate gradient in petroleum ether. When the appropriate fractions were combined and the solvent was evaporated, two products were obtained.
p1; 967 mg, Yield 23.3%, MS (m / z): 295 (M + H-Boc) ⁺ ; ¹ H NMR (400 MHz, cdcl3) δ 8.94 (d, J = 1.8, 1H), 8.85 ( d, J = 1.8, 1H), 7.54 (s, 1H), 5.64-5.55 (m, 1H), 4.15-4.10 (m, 1H), 3.95-3.89 (m, 1H), 3.87-3.79 (m, 1H ), 3.74-3.68 (m, 1H), 3.60-3.53 (m, 1H), 3.02-2.87 (m, 2H), 1.54 (d, J = 6.4, 3H), 1.41 (s, 9H).
p2; 869 mg, 21% yield.MS (m / z): 295 (M + H-Boc) ⁺ ; ¹ H NMR (400 MHz, cdcl3) δ 8.93 (d, J = 1.7, 1H), 8.86 ( d, J = 1.7, 1H), 7.52 (s, 1H), 5.73-5.63 (m, 1H), 4.06-3.97 (m, 1H), 3.95-3.89 (m, 1H), 3.86-3.79 (m, 1H ), 3.78-3.71 (m, 1H), 3.59-3.51 (m, 1H), 3.02-2.94 (m, 1H), 2.92-2.83 (m, 1H), 1.50 (d, J = 6.5, 3H), 1.45 (s, 9H).

Intermediate 36
2- (1,1-Dimethyl-1,3-dihydroisobenzofuran-5-yl) -4,4,5,5-tetramethyl-1,3,2-dioxaborolane

(A) 2- (4-Bromo-2- (hydroxymethyl) phenyl) propan-2-ol

A solution of 5-bromoisobenzofuran-1 (3H) -one (4.26 g, 20 mmol) in dry tetrahydrofuran (100 mL) was cooled in an ice bath under argon. Methyl magnesium bromide (3M in diethyl ether, 20 mL, 60 mmol) was added dropwise and the resulting mixture was allowed to warm to room temperature overnight. The reaction mixture was cooled to 0 ° C. and saturated aqueous ammonium chloride was added. The mixture was extracted with ethyl acetate and the organic phase was dried over magnesium sulfate, filtered and concentrated. The crude product was filtered through a silica gel plug with 50% ethyl acetate in heptane to give 2- (4-bromo-2- (hydroxymethyl) phenyl) propan-2-ol as a white solid. (1.76 g, 36% yield).
¹ H NMR (400 MHz, cdcl ₃ ) δ 7.48 (d, J = 2.2, 1H), 7.37 (dd, J = 8.5, 2.2, 1H), 7.16 (d, J = 8.5, 1H), 4.79 (s, 2H), 2.83 (s, 2H), 1.65 (s, 6H).

(B) 2- (4-Bromo-2- (hydroxymethyl) phenyl) propan-2-ol (1.76 g, in 5-bromo-1,1-dimethyl-1,3-dihydroisobenzofuran toluene (25 mL) To a suspension of 7.2 mmol) phosphoric acid (11.2 g, 115 mmol) was added. The mixture was stirred at 80 ° C. for 3 hours. The reaction was cooled to room temperature and then to 0 ° C. The mixture was basified with 2M sodium hydroxide and then extracted with ethyl acetate (x2). The organic phase was dried over magnesium sulfate, filtered and concentrated to give 5-bromo-1,1-dimethyl-1,3-dihydroisobenzofuran (1.62 g) as an oil. Yield 99%.
¹ H NMR (400 MHz, cdcl ₃ ) δ 7.38 (d, J = 8.0, 1H), 7.33 (s, 1H), 6.98 (d, J = 8.0, 1H), 5.02 (s, 2H), 1.48 (s , 6H).

(C) 2- (1,1-Dimethyl-1,3-dihydroisobenzofuran-5-yl) -4,4,5,5-tetramethyl-1,3,2-dioxaborolane in anhydrous dioxane (80 mL) 5-Bromo-1,1-dimethyl-1,3-dihydroisobenzofuran (1.62 g, 7.2 mmol), bis (pinacolato) diboron (2.69 g, 10.6 mmol), Pd (dppf) Cl ₂ (205 mg, 0.28 mmol) , And KOAc (2.09 g, 21.3 mmol) was heated at 100 ° C. for 4 h. The reaction mixture was filtered and the solid was washed with CH ₂ Cl ₂ . The filtrate was concentrated in vacuo and purified by silica gel chromatography eluting with hexane-100% EtOAc (gradient) to give 1.9 g (97% yield) of crude product.
¹ H NMR (400 MHz, cdcl ₃ ) δ 7.73 (d, J = 7.5, 1H), 7.66 (s, 1H), 7.13 (d, J = 7.5, 1H), 5.06 (s, 2H), 1.49 (s , 6H), 1.34 (s, 12H).

Intermediate 37
2- (1,1-Dimethylisochroman-6-yl) -4,4,5,5-tetramethyl-1,3,2-dioxaborolane

(A) 1,1-dimethylisochroman-6-yl trifluoromethanesulfonate 1,1-dimethylisochroman-6-ol (1.78 g, 10 mmol) and triethylamine (3.03 g, in dry dichloromethane (30 mL) under argon. 30 mmol) of trifluoromethanesulfonic anhydride (8.46 g, 30 mmol) was added dropwise at 0 ° C. The resulting mixture was slowly warmed to 20 ° C. over 16 hours, then poured into saturated aqueous sodium bicarbonate (50 mL) and extracted with dichloromethane (2 × 30 mL). The combined organic extracts were washed with brine (50 mL), dried over Na ₂ SO ₄ and evaporated in vacuo. The residue was purified by silica gel chromatography eluting with ethyl acetate in hexane (10% -30%) to give 1,1-dimethylisochroman-6-yl trifluoromethanesulfonate as an oil that was Used directly in the process.

(B) 2- (1,1-Dimethylisochroman-6-yl) -4,4,5,5-tetramethyl-1,3,2-dioxaborolane 1,1-dimethylisoquinone in anhydrous dioxane (80 mL) A mixture of Roman-6-yl trifluoromethanesulfonate, bis (pinacolato) diboron (3.81 g, 12 mmol), Pd (dppf) Cl ₂ (292 mg, 0.4 mmol), and KOAc (2.94 g, 30 mmol) at 100 ° C. for 4 hours. Heated. The reaction mixture was filtered and the solid was washed with CH ₂ Cl ₂ . The filtrate was concentrated in vacuo and purified by silica gel chromatography eluting with hexane-100% EtOAc (gradient) to give 2.88 g (100% yield) of an oil.
¹ H NMR (400 MHz, cdcl ₃ ) δ 7.18-7.13 (m, 1H), 7.08-7.02 (m, 1H), 7.00-6.97 (m, 1H), 3.93 (t, J = 5.6, 2H), 2.83 (t, J = 5.4, 2H), 1.51 (s, 6H), 1.25 (s, 12H).

Intermediate 38
3- (4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl) azetidine-1-carboxylate tert-butyl

(A) tert-butyl 3- (4-bromophenyl) azetidine-1-carboxylate in air, 4-bromophenylboronic acid (2.4 g, 12 mmol), NiI ₂ (94 mg, 0.3 mmol), trans-2- Aminocyclohexanol hydrochloride (45 mg, 0.3 mmol) and sodium hexamethyldisilazane (2.2 g, 12 mmol) were mixed in a microwave vial. The mixture was capped and placed under a nitrogen atmosphere. Isopropyl alcohol (10 mL) was added and the mixture was stirred for 5-10 minutes under nitrogen. 1-Boc-3-iodoazetidine (1.7 g, 6 mmol) was added to isopropyl alcohol (1 mL + 1 mL for rinsing). The nitrogen atmosphere was removed and the mixture was heated to 80 ° C. under microwave irradiation. Heating was maintained at 80 ° C. for 30 minutes. After cooling, the mixture was diluted with ethanol (10 mL) and filtered through a celite plug. The filter cake was washed with ethanol (2 × 5 mL) and the filtrate was concentrated in vacuo to leave a crude oil. The oil was purified by preparative thin layer chromatography using EtOAc / hexane (1:10) as the eluent to yield 724 mg (yield) of tert-butyl 3- (4-bromophenyl) azetidine-1-carboxylate. Rate 38%). MS (m / z): 212 (M + H-Boc) ^<+> .
¹ H NMR (400 MHz, CDCl ₃ ) δ 7.47 (d, J = 8.5, 2H), 7.18 (d, J = 8.3, 2H), 4.34-4.29 (m, 2H), 3.94-3.90 (m, 2H) , 3.72-3.63 (m, 1H), 1.46 (s, 9H).

(B) 3- (4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl) azetidine-1-carboxylate in anhydrous dioxane (30 mL) Tert-Butyl 3- (4-bromophenyl) azetidine-1-carboxylate (0.72 g, 2.3 mmol), bis (pinacolato) diboron (0.88 g, 3.45 mmol), Pd (dppf) Cl ₂ (67 mg, 0.09 mmol) , And KOAc (0.68 g, 6.9 mmol) was heated at 100 ° C. for 4 h. The reaction mixture was filtered and the solid was washed with CH ₂ Cl ₂ . The filtrate was concentrated in vacuo to give tert-butyl crude 3- (4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl) azetidine-1-carboxylate. 0.83 g (100% yield) was obtained and used directly in the next step. MS (m / z): 260 (M + H-Boc) ^<+> .

Intermediate 39
1- (4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl) cyclobutanol

The title compound was prepared according to the procedure for intermediate 15 (B). ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.83 (d, 2H), 7.51 (d, 2H), 2.61-2.53 (m, 2H), 2.42-2.34 (m, 2H), 2.20 (s, 1H), 2.06-2.01 (m, 1H), 1.76-1.64 (m, 1H), 1.35 (s, 12H).

Intermediate 40
4- (4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl) piperidine hydrochloride

(A) tert-Butyl 4- (4-bromophenyl) piperidine-1-carboxylate
To a solution of 4- (4-bromophenyl) piperidine (2.4 g, 10 mmol) and Et ₃ N (1.4 mL, 10.5 mmol) in CH ₂ Cl ₂ (30 mL) at 0 ° C. was added di-tert-butyl dicarbonate (2.29 g , 10.5 mmol) in CH ₂ Cl ₂ (20 mL) was added dropwise. The reaction mixture was stirred at room temperature for 4 hours. The reaction was then washed with NaHCO ₃ (25 mL), H ₂ O (25 mL) and brine (25 mL), dried over Na ₂ SO ₄ and concentrated to give a crude oil. MS (m / z): 286 (Mt-butyl) ^<+> .

(B) tert-butyl 4- (4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl) piperidine-1-carboxylate
To a solution of tert-butyl 4- (4-bromophenyl) piperidine-1-carboxylate (10 mmol) in DMSO (1000 mL), KOAc (2.95 g, 30 mmol), PdCl ₂ (dppf) (1098 mg, 1.5 mmol), and 4 4,4 ′, 4 ′, 5,5,5 ′, 5′-octamethyl-2,2′-bi (1,3,2-dioxaborolane) (5.08 g, 20 mmol) was added. The mixture was stirred at 80 ° C. for 6 hours under N ₂ atmosphere. The mixture was poured into water (150 mL) and extracted with EA. The organic phase was washed with brine and concentrated to give a crude product. The crude product was purified by column chromatography (CH ₂ Cl ₂ : MeOH = 20: 1) to give a yellow oil. MS (m / z): 288 (MC 5 H 9 O 2 + H) +.

(C) 4- (4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl) piperidine hydrochloride
4- (4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl) piperidine-1-carboxylate tert-butyl (10 mmol) dissolved in EA (10 mL) To this solution was added a solution of 5N HCl / EA (10 mL). The reaction mixture was stirred at 20 ° C. for 8 hours. The reaction mixture was then concentrated to give the crude product as a white solid. MS (m / z): 288 (M + H) ^<+> .

Intermediate 41
1-Methyl-5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) indoline-2-one

(A) 5-Bromo-1-methylindoline-2-one
To a solution of 5-amino-1-methylindoline-2-one (811 mg, 5 mmol) in 40 mL of 40% aqueous HBr at 0 ° C. was added a solution of NaNO ₂ (380 mg, 55 mmol) in H ₂ O (3 mL). The mixture was stirred at 0 ° C. for 40 minutes. The mixture was then slowly poured into an aqueous solution of CuBr (1.51 g, 10.5 mmol) in HBr (10 mL) at 0 ° C. The reaction mixture was heated to 60 ° C. and stirred for 2 hours. The mixture was cooled, basified with 2N NaOH aqueous solution until pH = 8-9, and extracted with EA. The organic phase was washed with H ₂ O and brine, concentrated and purified by column chromatography (EA: PE = 1: 1) to give the crude as a solid. MS (m / z): 228 (M + 2) ^<+> .

(B) 1-Methyl-5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) indoline-2-one
To a solution of 5-bromo-1-methylindoline-2-one (140 mg, 0.62 mmol) in DMSO (10 mL), KOAc (183 mg, 1.86 mmol), PdCl ₂ (dppf) (68 mg, 0.093 mmol), and 4,4 4,4 ′, 4 ′, 5,5,5 ′, 5′-octamethyl-2,2′-bi (1,3,2-dioxaborolane) (315 mg, 1.24 mmol) was added. The mixture was stirred at 80 ° C. for 6 hours under N ₂ atmosphere. The reaction was poured into water (150 mL) and extracted with EA. The organic phase was washed with brine and concentrated to give a crude product. The crude product was purified by column chromatography (EA: PE = 1: 3) to give a yellow oil. MS (m / z): 274 (M + H) ^<+> .

Intermediate 42
(6- (Dimethylamino) -5-methylpyridin-3-yl) boronic acid

(A) 5-Bromo-N, N, 3-trimethylpyridin-2-amine In a tube, add 5-bromo-2-fluoro-3-methylpyridine (475 mg, 2.5 mmol) in NMP (5 mL) to dimethylamine. Hydrochloride (408 mg, 5 mmol) and N-ethyl-N-isopropylpropan-2-amine (1.68 mL, 10 mmol) were added. The tube was sealed and heated in the microwave at 180 ° C. for 1 hour. TLC and LC-Ms showed that the reaction was complete and the desired compound was detected. The reaction mixture was poured into H ₂ O (30 mL) and extracted with EA. The organic phase was washed with water and brine, dried and concentrated to give a yellow oil. MS (m / z): 217 (M + 2) ^<+> .

(B) 6- (Dimethylamino) -5-methylpyridin-3-ylboronic acid
To a solution of 5-bromo-N, N, 3-trimethylpyridin-2-amine (475 mg, 2.21 mmol) in DMSO (10 mL), KOAc (650 mg, 6.63 mmol), PdCl ₂ (dppf) (242 mg, 0.33 mmol), And 4,4,4 ′, 4 ′, 5,5,5 ′, 5′-octamethyl-2,2′-bi (1,3,2-dioxaborolane) (1.12 g, 4.42 mmol) were added. The mixture was stirred at 80 ° C. for 6 hours under N ₂ atmosphere. The reaction mixture was poured into water (150 mL) and extracted with EA. The organic phase was washed with brine and concentrated to give a crude product. The crude product was purified by column chromatography (EA: PE = 1: 1) to give a yellow oil. MS (m / z): 181 (M + H) ^<+> .

Intermediate 43
1- (2-Methyl-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl) piperazine hydrochloride

(A) tert-butyl 4- (4-bromo-2-methylphenyl) piperazine-1-carboxylate
To a solution of 1- (4-bromo-2-methylphenyl) piperazine (2.55 g, 10 mmol) and Et ₃ N (1.4 mL, 10.5 mmol) in CH ₂ Cl ₂ (30 mL) at 0 ° C. with di-tert-butyldi A solution of carbonate (2.29 g, 10.5 mmol) in CH ₂ Cl ₂ (20 mL) was added dropwise. The reaction mixture was stirred at room temperature for 4 hours. The reaction mixture was then washed with aqueous NaHCO ₃ (25 mL), H ₂ O (25 mL) and brine (25 mL), dried over Na ₂ SO ₄ and concentrated to give a yellow oil. MS (m / z): 357 (M + H) ^<+> .

(B) tert-Butyl 4- (2-methyl-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl) piperazine-1-carboxylate
To a solution of tert-butyl 4- (4-bromo-2-methylphenyl) piperazine-1-carboxylate (10 mmol) in DMSO (100 mL), KOAc (2.95 g, 30 mmol), PdCl ₂ (dppf) (1098 mg, 1.5 mmol) ), And 4,4,4 ′, 4 ′, 5,5,5 ′, 5′-octamethyl-2,2′-bi (1,3,2-dioxaborolane) (5.08 g, 20 mmol). The mixture was stirred at 80 ° C. for 6 hours under N ₂ atmosphere. The reaction mixture was poured into water (150 mL) and extracted with EA. The organic phase was washed with brine and concentrated to give a crude product. The crude product was purified by column chromatography (PE: EA = 5: 1) to give a yellow oil. MS (m / z): 403 (M + H) ^<+> .

(C) 1- (2-Methyl-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl) piperazine hydrochloride
4- (2-methyl-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl) piperazine-1-carboxylate tert-butyl (10 mmol) was added to EA ( 10 mL) and to this solution was added a solution of 5N HCl / EA (10 mL). The reaction mixture was stirred at 20 ° C. for 8 hours. The reaction mixture was concentrated to give a white solid. MS (m / z): 303 (M + H) ^<+> .

Intermediate 44
1-Methyl-6- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1,2,3,4-tetrahydroquinoline

(A) 1-methyl-1,2,3,4-tetrahydroquinoline
To a solution of 1,2,3,4-tetrahydroquinoline (1.33 g, 10 mmol) in THF (50 mL) was added NaH (60%, 600 mg, 15 mmol) at 0 ° C. and the mixture was stirred for 20 minutes. Then CH ₃ I (1.71 g, 15 mmol) was added dropwise to the reaction and the mixture was stirred at room temperature for 16 h. The reaction solution was washed with NH ₄ Cl saturated aqueous solution and extracted with EA. The organic phase was washed with water and brine, concentrated and purified by column chromatography (EA: PE = 1: 3) to give a yellow oil. MS (m / z): 148 (M + H) ^<+> .

(B) 6-Bromo-1-methyl-1,2,3,4-tetrahydroquinoline
To a solution of 1-methyl-1,2,3,4-tetrahydroquinoline (877 mg, 5.96 mmol) in THF (20 mL) was added NBS (1.06 g, 5.96 mmol) at −78 ° C., and the mixture was added at −78 ° C. Stir for 3 hours at room temperature for 16 hours. The reaction mixture was washed with saturated aqueous Na ₂ CO _{3 and} extracted with EA. The organic phase was washed with water and brine and concentrated to give a yellow oil. MS (m / z): 403 (M + H) ^<+> .

(C) 1-methyl-6- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1,2,3,4-tetrahydroquinoline
To a solution of 6-bromo-1-methyl-1,2,3,4-tetrahydroquinoline (1.35 g, 5.96 mmol) in DMSO (50 mL), KOAc (1.75 g, 17.88 mmol), PdCl ₂ (dppf) (651 mg, 0.85 mmol), and 4,4,4 ′, 4 ′, 5,5,5 ′, 5′-octamethyl-2,2′-bi (1,3,2-dioxaborolane) (3.03 g, 11.92 mmol). added. The mixture was stirred at 80 ° C. for 6 hours under N ₂ atmosphere. The reaction mixture was poured into water (150 mL) and extracted with EA. The organic phase was washed with brine and concentrated to give a crude product. The crude product was purified by column chromatography (PE: EA = 1: 1) to give a yellow oil. MS (m / z): 274 (M + H) ^<+> .

Intermediate 45
1-methyl-4- (2-methyl-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl) piperazine

1- (2-Methyl-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl) piperazine hydrochloride (1.02 g, 3 mmol) was added to 37% aqueous formaldehyde (30 mL) and acetic acid (1.8 g, 30 mmol). Sodium acetate (2.46 g, 30 mmol) was added and the mixture was cooled in an ice / water bath. Sodium cyanoborohydride (377 mg, 6 mmol) was added and the mixture was stirred for 3 hours. Saturated aqueous NaHCO ₃ was added until the mixture was basic. The mixture was extracted with DCM (x3) and the combined extracts were dried over MgSO ₄ and concentrated to give a yellow solid. MS (m / z): 317 (M + H) ^<+> .

Intermediate 46
1-Methyl-5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) indoline

(A) 1-Methyl-5-nitroindoline
5-Nitroindoline (1.64 g, 10 mmol) was dissolved in 37% aqueous formaldehyde (50 mL) and acetic acid (6.0 g, 100 mmol). Sodium acetate (8.2 g, 100 mmol) was added and the mixture was cooled in an ice / water bath. Sodium cyanoborohydride (1.26 g, 20 mmol) was added and the mixture was stirred for 9 hours. Saturated aqueous NaHCO ₃ was added until the mixture was basic. The mixture was extracted with DCM (x3) and the combined extracts were dried over MgSO ₄ and concentrated to give a yellow solid. MS (m / z): 179 (M + H) ^<+> .

(B) 1-Methylindoline-5-amine
To a solution of 1-methyl-5-nitroindoline (10 mmol) in MeOH (30 mL) was added Pd / C (1 g) and the mixture was stirred at 20 ° C. for 4 hours under 1 atm H ₂ atmosphere. The reaction mixture was filtered and the filtrate was concentrated and purified by column chromatography (EA: PE = 1: 1) to give a gray solid. MS (m / z): 149 (M + H) ^<+> .

(C) 5-Bromo-1-methylindoline
To a solution of 1-methylindoline-5-amine (960 mg, 6.48 mmol) in 10 mL of aqueous HBr (40%) at 0 ° C. was added a solution of NaNO ₂ (492 mg, 7.13 mmol) in H ₂ O (2 mL). . The mixture was stirred at 0 ° C. for 40 minutes. The mixture was poured into an aqueous solution of CuBr (1.95 g, 13.6 mmol) in HBr (10 mL) at 0 ° C. The reaction mixture was then heated to 60 ° C. and stirred for 2 hours. After cooling the mixture, it was basified with 2M aqueous NaOH until pH = 8-9 and extracted with EA. The organic phase was washed with H ₂ O and brine, concentrated and purified by column chromatography (EA: PE = 1: 5) to give a yellow solid. MS (m / z): 214 (M + 2) ^<+> .

(D) 1-Methyl-5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) indoline
To a solution of 5-bromo-1-methylindoline (47 mg, 0.22 mmol) in DMSO (5 mL), KOAc (65.3 mg, 0.66 mmol), PdCl ₂ (dppf) (24 mg, 0.35 mmol), and 4,4,4 ′ , 4 ′, 5,5,5 ′, 5′-octamethyl-2,2′-bi (1,3,2-dioxaborolane) (113 mg, 0.44 mmol) was added. The mixture was stirred at 80 ° C. for 6 hours under N ₂ atmosphere. The reaction mixture was poured into water (150 mL) and extracted with EA. The organic phase was washed with brine and concentrated to give a crude product. The crude product was purified by column chromatography (EA: PE = 1: 20) to give a white solid. MS (m / z): 262 (M + H) ^<+> .

Intermediate 47
(S) -4- (hydroxymethyl) -1-((S) -1-phenylethyl) pyrrolidin-2-one

(S)-5-オキソ-1-((S)-1-フェニルエチル)ピロリジン-3-カルボン酸(520mg、2.23mol)のTHF(10mL)溶液に、0℃でボランジメチルスルフィド錯体(テトラヒドロフラン中の2M、1.67mL、3.34mmol)を滴下し、この混合物を25℃で3時間撹拌した。この反応物をNa₂CO₃飽和水溶液によりクエンチし、EAにより抽出した。有機相を水及びブラインにより洗浄し、濃縮すると黄色油状物が得られた。MS(m/z):220(M+H)⁺。

To a solution of (S) -5-oxo-1-((S) -1-phenylethyl) pyrrolidine-3-carboxylic acid (520 mg, 2.23 mol) in THF (10 mL) at 0 ° C., borane dimethyl sulfide complex (in tetrahydrofuran) Of 2M, 1.67 mL, 3.34 mmol) was added dropwise and the mixture was stirred at 25 ° C. for 3 h. The reaction was quenched with saturated aqueous Na ₂ CO _{3 and} extracted with EA. The organic phase was washed with water and brine and concentrated to give a yellow oil. MS (m / z): 220 (M + H) ^<+> .

Intermediate 48
(R) -4- (hydroxymethyl) -1-((R) -1-phenylethyl) pyrrolidin-2-one

The title compound was prepared according to the procedure for Intermediate 47. MS (m / z): 220 (M + H) ^<+> .

Intermediate 49
(2-Methyl-2- (4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl) propyl) carbamate tert-butyl

(A) 2-Methyl-2- (4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl) propan-1-amine
To a mixture of LiAlH ₄ (57 mg, 1.5 mmol) in dry THF (8 mL) under N ₂ atmosphere was added 2-methyl-2- (4- (4,4,5,5-tetramethyl-1, A solution of 3,2-dioxaborolan-2-yl) phenyl) propanenitrile (271 mg, 1 mmol) in dry THF (2.0 mL) was added dropwise. After 30 minutes, the cooling bath was removed and the mixture was stirred at room temperature for 3 hours. The mixture was again cooled to 0 ° C. and carefully quenched with 2M aqueous NaOH (0.5 mL). The resulting suspension was filtered and the filter cake was rinsed with THF. The filtrate was concentrated to give a white oil. MS (m / z): 276 (M + H) ^<+> .

(B) tert-butyl 2-methyl-2- (4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl) propylcarbamate
2-Methyl-2- (4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl) propan-1-amine (1 mmol) and Et ₃ N (153 uL, To a solution of 1.1 mmol) in DCM (3 mL) was added dropwise a solution of di-tert-butyl dicarbonate (240 mg, 1.1 mmol) in DCM (2 mL) at 0 ° C. The reaction mixture was stirred at room temperature for 4 hours. The reaction mixture was then washed with aqueous NaHCO ₃ (25 mL), H ₂ O (25 mL) and brine (25 mL), dried over Na ₂ SO ₄ and concentrated to give a yellow oil. MS (m / z): 376 (M + H) ^<+> .

Intermediate 50
3- (4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl) pentan-3-ol

(A) 3- (4-Bromophenyl) pentan-3-ol
To a solution of methyl 4-bromobenzoate (2.15 g, 10 mmol) in THF (60 mL) was added dropwise ethylmagnesium bromide (3 M in ether, 8 mL, 24 mmol) at 0 ° C., and the mixture was stirred at 25 ° C. for 18 hours. did. The reaction mixture was quenched with saturated aqueous NH ₄ Cl and extracted with EA. The organic phase was washed with water and brine, dried, concentrated and purified by column chromatography (EA: PE = 1: 3) to give a yellow oil. MS (m / z): 185 (M-2 ethyl) ^<+> .

(B) 3- (4- (4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl) pentan-3-ol
To a solution of 3- (4-bromophenyl) pentan-3-ol (2.03 g, 8.35 mmol) in dioxane (85 mL), KOAc (2.47 g, 25.1 mmol), PdCl ₂ (dppf) (1.04 g, 1.25 mmol), And 4,4,4 ′, 4 ′, 5,5,5 ′, 5′-octamethyl-2,2′-bi (1,3,2-dioxaborolane) (3.18 g, 12.5 mmol) were added. The mixture was stirred at 100 ° C. for 3 hours under N ₂ atmosphere. The reaction mixture was poured into water (250 mL) and extracted with EA. The organic phase was washed with brine and concentrated to give a crude product. The crude product was purified by column chromatography (EA: PE = 1: 4) to give a yellow solid. MS (m / z): 217 (MC 4 H 11 O + H) +.

Intermediate 51
N, N-dimethyl-1- (4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl) ethanamine

(A) 1- (4-Bromophenyl) -N-methylethanamine
1- (4-Bromophenyl) ethanamine (1 g, 5 mmol) was dissolved in 37% aqueous formaldehyde (1.22 mL, 15 mmol) and MeOH (15 mL). Sodium acetate (1.64 g, 20 mmol) was added and the mixture was cooled in an ice / water bath. Sodium cyanoborohydride (1.25 g, 20 mmol) was added and the mixture was stirred for 24 hours. Saturated aqueous sodium bicarbonate was added until the mixture was basic. The mixture was extracted with DCM (x3) and the combined extracts were dried over MgSO ₄ and concentrated to give a yellow oil.

(B) 1- (4-Bromophenyl) -N, N-dimethylethanamine
1- (4-Bromophenyl) -N-methylethanamine (5 mmol) in 37% aqueous formaldehyde (1.22 mL) and DCE (15 mL) was added to NaBH (AcO) ₃ (2.12 g, 20 mmol) at 0 ° C. The mixture was stirred for 24 hours. Saturated aqueous sodium bicarbonate was added until the mixture was basic. The mixture was extracted with DCM (× 2), and concentrated dehydrating the combined extracts over MgSO _4, thin layer chromatography and purified by (DCM:: MeOH = 10 1 ), a yellow solid was obtained. MS (m / z): 230 (M + 2) ^<+> .

(C) N, N-dimethyl-1- (4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl) ethanamine
To a solution of 1- (4-bromophenyl) -N, N-dimethylethanamine (534 mg, 2.34 mmol) in dioxane (25 mL), KOAc (691 mg, 7.03 mmol), PdCl ₂ (dppf) (286 mg, 0.35 mmol), And 4,4,4 ′, 4 ′, 5,5,5 ′, 5′-octamethyl-2,2′-bi (1,3,2-dioxaborolane) (891 mg, 3.51 mmol) were added. The mixture was stirred at 100 ° C. for 3 hours under N ₂ atmosphere. The reaction mixture was poured into water (250 mL) and extracted with EA. The organic phase was washed with brine and concentrated to give a crude product. The crude product was purified by column chromatography (EA: PE = 1: 4) to give a yellow solid. MS (m / z): 276 (M + H) ^<+> .

Intermediate 52
2- (4- (1-methoxyethyl) phenyl) -4,4,5,5-tetramethyl-1,3,2-dioxaborolane

(A) 1- (4-Bromophenyl) ethanol
To a solution of 1- (4-bromophenyl) ethanone (1.99 g, 10 mmol) in EtOH (30 mL) at 0 ° C. was added NaBH ₄ (1.14 g, 30 mmol) in small portions, then the mixture was added at 0 ° C. Stir for minutes. Since the completion of the reaction was shown by TLC, the mixture (cold) was poured into ice water, neutralized with 1N HCl solution until pH = 6-7, and extracted with EA. The organic phase was washed with brine, dried, concentrated and purified by silica gel chromatography (eluting with PE / EA = 5: 1 → 1: 1) to give the product as a white oil. MS (m / z): 284 (M-OH + H) ^<+> .

(B) 1-Bromo-4- (1-methoxyethyl) benzene
To a solution of 1- (4-bromophenyl) ethanol (1.92 g, 9.95 mmol) in DMF (30 mL) was added NaH (60%, 597 mg, 14.93 mmol) at 0 ° C., and the mixture was stirred at 0 ° C. for 30 min. . To the reaction was added CH ₃ I (1.67 g, 11.94 mmol) and the mixture was stirred at 20 ° C. for 24 hours. The reaction was quenched with saturated aqueous NH ₄ Cl and extracted with EA (20 mL ^* 3). The organic phase was washed with 30 mL water and brine, concentrated and purified by column chromatography (EA: PE = 1: 4) to give a brown solid.

(C) 2- (4- (1-methoxyethyl) phenyl) -4,4,5,5-tetramethyl-1,3,2-dioxaborolane
To a solution of 1-bromo-4- (1-methoxyethyl) benzene (1.29 g, 6 mmol) in dioxane (15 mL), KOAc (1.77 g, 19 mmol), PdCl ₂ (dppf) (700 mg, 0.9 mmol), and 4, 4,4 ′, 4 ′, 5,5,5 ′, 5′-octamethyl-2,2′-bi (1,3,2-dioxaborolane) (2.29 g, 9 mmol) was added. The mixture was stirred at 100 ° C. for 3 hours under N ₂ atmosphere. The mixture was poured into water (250 mL) and extracted with EA. The organic phase was washed with brine and concentrated to give a crude product. The crude product was purified by column chromatography (EA: PE = 1: 4) to give a yellow solid. MS (m / z): 231 (M-MeO + H) ^<+> .

Intermediate 53
Tert-butyl (2-methyl-1- (4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl) propyl) carbamate

(A) 1- (4-Bromophenyl) -2-methylpropan-1-one
To a solution of 1- (4-bromophenyl) ethanone (1.99 g, 10 mmol) in THF (50 mL) was added NaH (60%, 880 mg, 22 mmol) at 0 ° C. and the mixture was stirred at 0 ° C. for 30 min. To the reaction was added CH ₃ I (1.37 mLg, 22 mmol) and the mixture was stirred at 20 ° C. for 24 hours. The reaction was quenched with saturated aqueous NH ₄ Cl and extracted with EA (20 mL ^* 3). The organic phase was washed with 30 mL water and brine, concentrated and purified by column chromatography (DCM: MeOH = 50: 1) to give a brown solid. MS (m / z): 230 (M + 2) ^<+> .

(B) 1- (4-Bromophenyl) -2-methylpropan-1-amine
To a solution of 1- (4-bromophenyl) -2-methylpropan-1-one (1.83 g, 8.06 mmol) in MeOH (50 mL), NH ₃ / MeOH (7N, 11.5 mL, 80.6 mmol) and Ti (OEt) ₄ (9.19 g, 40.3 mmol) was added at room temperature. The reaction mixture was stirred at room temperature for 18 hours. The reaction was then cooled to 0 ° C. and NaBH ₄ (1.06 g, 32.24 mmol) was added. The mixture was warmed to room temperature and stirred for 3 hours. The reaction mixture was poured into 2M aqueous NH ₃ (900 mL) and then filtered. The filtrate was extracted with EA (3 × 50 mL) and the combined extracts were washed with water and brine, dried over Na ₂ SO ₄ , filtered and concentrated to give a yellow oil. MS (m / z): 212 (M-NH 3 + H) +.

(C) tert-butyl 1- (4-bromophenyl) -2-methylpropylcarbamate
1- (4-Bromophenyl) -2-methylpropan-1-amine (1.07 g, 4.69 mmol) and Et ₃ N (718 uL, 5.16 mmol) in DCM (3 mL) at 0 ° C. with di-tert-butyl A solution of dicarbonate (240 mg, 5.16 mmol) in DCM (2 mL) was added dropwise. The reaction was stirred at room temperature for 4 hours. The reaction mixture was washed with aqueous NaHCO ₃ (25 mL), H ₂ O (25 mL), and brine (25 mL), dried over Na ₂ SO ₄ , concentrated and column chromatography (EA: PE = 1: 10). To give a yellow oil. MS (m / z): 274 (Mt-butyl + 2) ^<+> .

(D) tert-butyl 2-methyl-1- (4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl) propylcarbamate
To a solution of tert-butyl 1- (4-bromophenyl) -2-methylpropylcarbamate (1.17 g, 3.56 mmol) in dioxane (50 mL) was added KOAc (1.05 g, 10.69 mmol), PdCl ₂ (dppf) (446 mg, 0.54 mmol), and 4,4,4 ′, 4 ′, 5,5,5 ′, 5′-octamethyl-2,2′-bi (1,3,2-dioxaborolane) (1.36 g, 5.35 mmol). added. The mixture was stirred at 100 ° C. for 3 hours under N ₂ atmosphere. The reaction mixture was poured into water (250 mL) and extracted with EA. The organic phase was washed with brine and concentrated to give a crude product. The crude product was purified by column chromatography (PE: EA = 4: 1) to give a yellow oil. MS (m / z): 320 (Mt-butyl + H) ^<+> .

Intermediate 54
(S) -6-(((7-chloropyrido [3,4-b] pyrazin-5-yl) oxy) methyl) -4-methylmorpholin-3-one

(A) (S) -2-Chloro-N- (2,3-dihydroxypropyl) acetamide
To a solution of (S) -3-aminopropane-1,2-diol (1.82 g, 20 mmol) and Et ₃ N (3.34 mL, 24 mmol) in DCM (40 mL) at 0 ° C. in 2 mL of chloride in DCM (10 mL). -Chloroacetyl (2.49 g, 22 mol) was added dropwise. The reaction mixture was stirred at room temperature for 2 hours. The reaction solution was washed with saturated aqueous NH ₄ Cl (5 mL), H ₂ O (5 mL) and brine (5 mL), dried over Na ₂ SO ₄ and concentrated to give a yellow solid. MS (m / z): 150 (MH 2 O + H) +.

(B) (S) -6- (Hydroxymethyl) morpholin-3-one A stirred solution of potassium tert-butoxide (5.21 g, 36.7 mmol) in tert-butyl alcohol (60 mL) at room temperature under nitrogen was charged with tert- (S) -2-Chloro-N- (2,3-dihydroxypropyl) acetamide (2.46 g, 14.68 mmol) in butyl alcohol (100 mL) was added slowly. The mixture was then stirred for 1 hour, then MeOH (20 mL) and H ₂ O (1 mL) were added and the reaction mixture was stirred for an additional 20 minutes. The mixture was concentrated in vacuo and the residue was purified by flash column chromatography on silica gel with MeOH / EtOAc (20/80) to give a yellow oil. MS (m / z): 132 (M + H) ^<+> .

(C) (S) -6-((7-chloropyrido [4,3-b] pyrazin-5-yloxy) methyl) morpholin-3-one
To a solution of (S) -6- (hydroxymethyl) morpholin-3-one (1.86 g, 14.2 mmol) in DMF (60 mL) was added NaH (60%, 851 mg, 21.28 mmol) at 0 ° C. Stir at 15 ° C. for 15 minutes. Then 5,7-dichloropyrido [4,3-b] pyrazine (3.41 g, 17.02 mmol) was added and the mixture was stirred at 20 ° C. for 2 hours. The reaction is quenched with saturated aqueous NH ₄ Cl, extracted with EA (20 mL ^* 3), washed with water (30 mL) and brine, concentrated and column chromatography (H ₂ O: MeOH = 1: 1). ) To give a brown solid. MS (m / z): 295 (M + H) ^<+> .

(D) (S) -6-((7-chloropyrido [4,3-b] pyrazin-5-yloxy) methyl) -4-methylmorpholin-3-one
(S) -6-((7-chloropyrido [4,3-b] pyrazin-5-yloxy) methyl) morpholin-3-one (1.6 g, 5.43 mmol) in DMF (50 mL) at room temperature with NaH (60%, 261 mg, 6.52 mmol) and CH ₃ I (406 uL, 6.52 mmol) were added. The reaction was stirred at 20 ° C. for 1 hour. The reaction was quenched with saturated aqueous NH ₄ Cl, extracted with EA (20 mL × 3), washed with water (30 mL) and brine, concentrated and thin layer chromatographed (DCM: MeOH = 30: 1). To give a brown solid. MS (m / z): 309 (M + H) ^<+> .

Intermediate 55
N- (2- (4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl) propan-2-yl) acetamide

(A) N- (2- (4-Bromophenyl) propan-2-yl) acetamide
A solution of 2- (4-bromophenyl) propan-2-amine hydrochloride (251 mg, 1 mmol) and Et ₃ N (350 uL, 2.5 mmol) in DCM (10 mL) at 0 ° C. with acetyl chloride (86.4 mg, 1.1 mmol). mmol) was added. The reaction mixture was stirred at room temperature for 4 hours. The reaction solution was washed with aqueous NaHCO ₃ (5 mL), H ₂ O (5 mL) and brine (5 mL), dried over Na ₂ SO ₄ and concentrated to give a white solid. MS (m / z): 256 (M + H) ^<+> .

(B) N- (2- (4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl) propan-2-yl) acetamide
To a solution of N- (2- (4-bromophenyl) propan-2-yl) acetamide (1 mmol) in dioxane (10 mL), KOAc (299 mg, 3 mmol), PdCl ₂ (dppf) (80 mg, 0.1 mmol), and 4 4,4 ′, 4 ′, 5,5,5 ′, 5′-octamethyl-2,2′-bi (1,3,2-dioxaborolane) (381 mg, 1.5 mmol) was added. The mixture was stirred at 100 ° C. for 3 hours under N ₂ atmosphere. The reaction mixture was then poured into water (150 mL) and extracted with EA. The organic phase was washed with brine and concentrated to give a crude product. The crude product was purified by column chromatography (PE: EA = 4: 1) to give a yellow solid. MS (m / z): 304 (M + H) ^<+> .

Intermediate 56
4- (4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl) tetrahydro-2H-pyran-4-ol

(A) 4- (4-Bromophenyl) tetrahydro-2H-pyran-4-ol
To a solution of 1,4-dibromobenzene (2.36 g, 10 mmol) in THF (50 mL) at −78 ° C. was slowly added a solution of 2.4N n-BuLi (4.2 mL, 10.5 mmol) and the mixture was stirred for 30 minutes. At the same temperature, dihydro-2H-pyran-4 (3H) -one (1.05 g, 10 mmol) was added. The reaction mixture was then slowly warmed to room temperature and stirred for 2 hours. After this time, the reaction was quenched with saturated aqueous NH ₄ Cl and extracted with EA. The organic phase was washed with water and brine and concentrated to give a yellow oil. MS (m / z): 241 (MH 2 O + H) +.

(B) 4- (4- (4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl) tetrahydro-2H-pyran-4-ol
To a solution of 4- (4-bromophenyl) tetrahydro-2H-pyran-4-ol (10 mmol) in dioxane (70 mL), KOAc (2.95 g, 30 mmol), PdCl ₂ (dppf) (816 mg, 1 mmol), and 4, 4,4 ′, 4 ′, 5,5,5 ′, 5′-octamethyl-2,2′-bi (1,3,2-dioxaborolane) (3.81 g, 15 mmol) was added. The mixture was stirred at 100 ° C. for 6 hours under N ₂ atmosphere. The reaction mixture was poured into water (150 mL) and extracted with EA. The organic phase was washed with brine and concentrated to give a crude product. The crude product was purified by column chromatography (PE: EA = 5: 1) to give a white solid. MS (m / z): 287 (MH 2 O + H) +.

Intermediate 57
2-Fluoro-N, N-dimethyl-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) aniline

The title compound was prepared according to the procedure for intermediate 15 (A). MS (m / z): 266 (M + H) ^<+> .

Intermediate 58
2- (4-Isopropoxy-3-methoxyphenyl) -4,4,5,5-tetramethyl-1,3,2-dioxaborolane

The title compound was prepared according to the procedure for intermediate 15 (A). MS (m / z): 293 (M + H) ^<+> .

Intermediate 59
2- (3-Isopropoxy-4-methoxyphenyl) -4,4,5,5-tetramethyl-1,3,2-dioxaborolane

The title compound was prepared according to the procedure for intermediate 15 (A). MS (m / z): 293 (M + H) ^<+> .

Intermediate 60
N, N, 2,6-tetramethyl-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) aniline

The title compound was prepared according to the procedure for Intermediate 15. MS (m / z): 276 (M + H) ^<+> .

Intermediate 61
N, N-dimethyl-1- (4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl) methanamine

The title compound was prepared according to the procedure for Intermediate 11. MS (m / z): 262 (M + H) ^<+> .

Intermediate 62
2-Methyl-2- (4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl) propane-1,3-diol

The title compound was prepared according to the procedure for intermediate 15 (B). MS (m / z): 275 (MH 2 O + H) +.

Intermediate 63
2-Methyl-2- (4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl) propanenitrile

(A) 2- (4-Bromophenyl) -2-methylpropanenitrile
To a solution of 2- (4-bromophenyl) acetonitrile (3.05 g, 15.56 mmol) in dry THF (25 mL) was added NaH (1.37 g, 34.23 mmol) at 0 ° C. After stirring at 0 ° C. for 30 min, MeI (6.63 g, 46.68 mmol) was added and the mixture was stirred at room temperature overnight. The mixture was quenched with saturated aqueous ammonium chloride (100 mL) and extracted with EA (200 mL). The organic phase was dried over Na ₂ SO ₄ , concentrated in vacuo, and purified by flash column chromatography (PE: EA = 1: 0 to 4: 1) to give 2.7 g of the desired compound. Yield: 77.4%.

(B) 2-Methyl-2- (4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl) propanenitrile
2- (4-Bromophenyl) -2-methylpropanenitrile (500 mg, 2.23 mmol) and 4,4,4 ′, 4 ′, 5,5,5 ′, 5′-octamethyl-2,2′-bi To a solution of (1,3,2-dioxaborolane) (850 mg, 3.34 mmol) in dioxane (20 mL) was added Pd (dppf) Cl ₂ (326 mg, 0.45 mmol) and KOAc (656 mg, 6.69 mmol). The reaction mixture was stirred at 100 ° C. for 4 hours under N ₂ atmosphere. The mixture was concentrated and the residue was purified by flash column chromatography (PE: EA = 1: 0 to 3: 1) to give 432 mg of product as a white solid. Yield: 71.4%. MS (m / z) = 272 (M + H) ^<+> .

Intermediate 64
N, N-dimethyl-5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) pyridin-2-amine

(A) 5-Bromo-N, N-dimethylpyridin-2-amine A mixture of 5-bromo-2-chloropyridine (3.5 g, 18.19 mmol) in dimethylamine (10 mL) was placed in a microwave reactor. Stir at 130 ° C. for 1 hour. The mixture was purified by flash column chromatography (MeOH: H ₂ O = 0: 1 to 10: 1) to give 2.9 g of crude product. MS (m / z) = 202 (M + H) ⁺ 203 (M + 2) ⁺ .

(B) N, N-dimethyl-5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) pyridin-2-amine The title compound is intermediate 63 (B) Prepared according to the procedure. MS (m / z) = 249 (M + H) ^<+> .

Intermediate 65
2- (4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl) propan-2-ol

(A) 2- (4-Bromophenyl) propan-2-ol
Under a N ₂ atmosphere, MeMgBr (9.3 mL, 27.90 mmol) was added at 0 ° C. to a solution of methyl 4-bromobenzoate (2.0 g, 9.30 mmol) in dry THF (60 mL). The mixture was stirred at room temperature for 2 hours. The mixture was quenched with saturated aqueous ammonium chloride (20 mL) and the reaction was partitioned between water (100 mL) and EA (200 mL). The organic phase was dried over Na ₂ SO ₄ and concentrated in vacuo, and the residue was purified by flash column chromatography (PE: EA = 1: 0 to 4: 1) to give 1.6 g of crude product.

(B) 2- (4- (4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl) propan-2-ol The title compound of intermediate 63 (B) Prepared according to procedure. MS (m / z) = 245 (M-18) ^<+> .

Intermediate 66
2-Methyl-2- (4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl) propanamide

(A) 2- (4-Bromophenyl) -2-methylpropanamide
To a solution of 2- (4-bromophenyl) -2-methylpropanenitrile (672 mg, 3.0 mmol) in EtOH (10 mL) was added saturated aqueous potassium carbonate (7.0 mL) and 30% H ₂ O ₂ (14 mL). The mixture was stirred at room temperature overnight. The mixture was partitioned between water (100 mL) and DCM (150 mL). The organic phase was dried over Na ₂ SO ₄ and concentrated to give 532 mg of the crude product as a white solid. MS (m / z) = 244 (M + H) ⁺ 245 (M + 2) ⁺ .

(B) 2-Methyl-2- (4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl) propanamide The title compound is intermediate 63 (B) Prepared according to the procedure. MS (m / z) = 290 (M + H) ^<+> .

Intermediate 67
(2- (4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl) propan-2-yl) carbamate tert-butyl

(A) 2- (4-Bromophenyl) propan-2-amine
To a solution of 2- (4-bromophenyl) -2-methylpropanamide (242 mg, 1 mmol) in MeCN / H ₂ O (4 mL / 4 mL), PhI (OCOCF ₃ ) ₂ (430 mg, 1 mmol) was added in one portion. . The mixture was stirred at room temperature overnight. This mixture was extracted with EA, the organic phase was dehydrated with Na ₂ SO ₄ and concentrated, and the residue was purified by column chromatography (PE: EA = 1: 0 to 1:10) to obtain the target compound. . MS (m / z) = 197 (M-17) ⁺ , 198 (M-16) ⁺ .

(B) tert-Butyl (2- (4-bromophenyl) propan-2-yl) carbamate
To a solution of 2- (4-bromophenyl) propan-2-amine (320 mg, 1.49 mmol) and Et ₃ N (302 mg, 2.98 mmol) in DCM (10 mL) at 0 ° C. (Boc) ₂ O (392 mg, 1.79 mmol). ) Was added. The mixture was stirred at room temperature overnight. The mixture was partitioned between water (300 mL) and DCM (150 mL). The organic phase was dried over Na ₂ SO ₄ and concentrated to give 436 mg of crude product. MS (m / z) = 197 (M-117) ⁺ , 200 (M-115) ⁺ .

(C) (2- (4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl) propan-2-yl) carbamate tert-butyl Prepared according to the procedure for intermediate 63 (B). MS (m / z) = 244 (M-118) ^<+> , 245 (M-117) ^<+> .

Intermediate 68
2- (4- (2-methoxypropan-2-yl) phenyl) -4,4,5,5-tetramethyl-1,3,2-dioxaborolane

To a solution of 2- (4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl) propan-2-ol (514 mg, 2.0 mmol) in MeOH (10 mL), DDQ (908 mg, 4.0 mmol) was added at 0 ° C. The mixture was stirred at room temperature overnight. The mixture was concentrated and the residue was purified by flash column chromatography (PE: EA = 20: 1-4: 1) to give 200 mg of product as a white solid.
¹ HNMR (400 MHz, CDCl ₃ ) δ 7.79 (d, J = 8.2 Hz, 2H), 7.40 (d, J = 8.3Hz, 2H), 3.06 (s, 3H), 1.51 (s, 6H), 1.33 ( s, 12H).

Intermediate 69
2,2-dimethyl-1- (4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl) propan-1-ol

(A) 1- (4-Bromophenyl) -2,2-dimethylpropan-1-one
NaH (3.2 g, 80.40 mmol) was added at 0 ° C. to a solution of 1- (4-bromophenyl) ethanone (4.0 g, 20.10 mmol) in dry THF (80 mL) under N ₂ atmosphere. After stirring at 0 ° C. for 30 min, MeI (11.4 g, 80.40 mmol) was added and the mixture was stirred at room temperature overnight. The mixture was quenched with saturated aqueous ammonium chloride (100 mL) and extracted with EA (200 mL). The organic phase was dried over Na ₂ SO ₄ and concentrated in vacuo to give 4.5 g of crude product.
¹ H NMR (400 MHz, CDCl ₃ ) δ 7.55-7.58 (m, 2H), 7.51-7.53 (m, 2H), 1.32 (s, 9H).

(B) 1- (4-Bromophenyl) -2,2-dimethylpropan-1-ol
Under a N ₂ atmosphere, LiAlH ₄ (0.92 g, 24.12) was added to a solution of 1- (4-bromophenyl) -2,2-dimethylpropan-1-one (4.5 g, 18.66 mmol) in dry THF (80 mL) at 0 ° C. mmol) was added. The mixture was stirred at 0 ° C. for 1 hour. The mixture was quenched with water (100 mL) and extracted with EA (300 mL). The organic phase was dried over Na ₂ SO ₄ and concentrated to give 3.9 g of product.
¹ H NMR (400 MHz, CDCl ₃ ) δ 7.42 (dd, J = 8.4 Hz, 1.3 Hz, 2H), 7.16 (dd, J = 8.2 Hz, 1.1 Hz, 2H), 4.33 (s, 1H), 0.89 ( s, 9H).

(C) 2,2-Dimethyl-1- (4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl) propan-1-ol Prepared according to the procedures for body 63 (B). MS (m / z) = 289 (M + H) ^<+> .
¹ H NMR (400 MHz, CDCl ₃ ) δ 7.74 (d, J = 7.9 Hz, 2H), 7.29 (d, J = 8.0 Hz, 2H), 4.38 (s, 1H), 1.33 (s, 12H), 1.25 -1.23 (m, 9H).

Intermediate 70
2-Methyl-1- (4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl) propan-1-ol

(A) 1- (4-Bromophenyl) -2-methylpropan-1-ol
To a solution of 4-bromobenzaldehyde (3.7 g, 20.0 mmol) in dry THF (80 mL) under N ₂ atmosphere was added isopropylmagnesium chloride (12 mL, 24.0 mmol) at 0 ° C. The mixture was stirred at 0 ° C. for 30 minutes. The mixture was then stirred for an additional 30 minutes at room temperature. The mixture was quenched with water (200 mL) and extracted with EA (200 mL). The organic phase was dried over Na ₂ SO ₄ and concentrated in vacuo to give 4.6 g of the title compound.
¹ H NMR (400 MHz, CDCl ₃ ) δ 7.36-7.40 (m, 2H), 7.15-7.10 (m, 2H), 4.25 (d, J = 6.6 Hz, 1H), 1.80-1.85 (m, 1H), 0.88 (d, J = 6.7 Hz, 3H), 0.72 (d, J = 6.8 Hz, 3H).

(B) 2-Methyl-1- (4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl) propan-1-ol The title compound is intermediate 63. Prepared according to procedure (B).
¹ H NMR (400 MHz, CDCl ₃ ) δ 7.77 (d, J = 8.1 Hz, 2H), 7.31 (d, J = 8.2 Hz, 2H), 4.38 (d, J = 6.6 Hz, 1H), 1.93-1.98 (m, 1H), 1.34 (s, 14H), 0.97 (d, J = 6.7 Hz, 3H), 0.80 (d, J = 6.8 Hz, 3H).

Intermediate 71
2- (Hydroxymethyl) -4-methylmorpholin-3-one

(A) 4-Methylmorpholin-3-one
To a suspension of 2- (methylamino) ethanol (8 mL, 0.1 mol) and NaOH (4.0 g, 0.1 mol) in DCM (100 mL) and water (100 mL) at 0 ° C. was added 2-chloroacetyl chloride (7.62 mL). , 0.1 mol) in DCM (150 mL) was added dropwise over 30 minutes and the mixture was stirred at room temperature for 72 hours. The mixture was then evaporated under reduced pressure. The residue was dissolved in EtOH (150 mL) and then KOH (5.6 g, 0.1 mol) was added. The mixture was stirred at 40 ° C. for 18 hours and then filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography (PE: EA = 1: 0 to 1: 0 to 0: 1) to give 5.78 g of the title compound. MS (m / z) = 116 (M + H) ^<+> .

(B) 2- (Hydroxymethyl) -4-methylmorpholin-3-one
Under a N ₂ atmosphere, n-BuLi (5 mL, 12.0 mmol) was added to a solution of DIPEA (1.21 g, 12.0 mmol) in dry THF (15 mL) at −78 ° C. The mixture was stirred at −78 ° C. for 15 minutes and added dropwise to a suspension of 4-methylmorpholin-3-one (1.15 g, 10.0 mmol) in dry THF (5 mL) over 5 minutes. The mixture was stirred at -78 ° C for 1 minute. Paraformaldehyde (0.36 g, 12 mmol) was added and the mixture was stirred at room temperature for 3 hours. The mixture was quenched with water (1 mL) and concentrated in vacuo and the residue was purified by flash column chromatography (DCM: MeOH = 1: 0 to 5: 1) to give 438 mg of product. MS (m / z) = 146 (M + H) ^<+> .
¹ H NMR (400 MHz, cdcl ₃ ) δ 4.14-4.12 (m, 1H), 4.07-4.02 (m, 1H), 3.93-3.80 (m, 3H), 3.63-3.57 (m, 1H), 3.18-3.14 (m, 1H), 2.98 (s, 3H).

Intermediate 72
2- (4- (1,1-difluoroethyl) phenyl) -4,4,5,5-tetramethyl-1,3,2-dioxaborolane

  The title compound was prepared according to the procedure for intermediate 15 (B).

Intermediate 73
2- (Hydroxymethyl) morpholin-3-one

  The title compound was prepared according to the procedure for intermediate 71 (B).

Intermediate 74
4,4,5,5-tetramethyl-2- (4- (3-methyloxetane-3-yl) phenyl) -1,3,2-dioxaborolane

(A) Diethyl 2- (4-bromophenyl) malonate
To a solution of DIPEA (2.23 g, 22 mmol) in dry THF (40 mL) was added n-BuLi (9.12 mL, 22 mmol) at −78 ° C. After stirring for 30 minutes, ethyl cyanoformate (5.0 g, 21 mmol) was added and the mixture was stirred at room temperature for 48 hours. The mixture was quenched with water (15 mL) and partitioned between 1N HCl (50 mL) and DCM (50 mL). The organic layer was dried over Na ₂ SO ₄ and concentrated in vacuo to give 7.1 g of the title compound.
¹ H NMR (400 MHz, cdcl ₃ ) δ 7.33-7.31 (m, 2H), 7.29-7.19 (m, 2H), 4.25-4.18 (m, 2H), 4.17-4.08 (m, 2H), 3.56 (s , 1H), 1.27-1.22 (m, 6H).

(B) 2- (4-Bromophenyl) -2-methylmalonate diethyl
To a solution of diethyl 2- (4-bromophenyl) malonate (7.1 g, 19.04 mmol) in dry THF (45 mL) was added NaH (1.0 g, 25.2 mmol) at 0 ° C. After stirring at 0 ° C. for 30 minutes, MeI (5.96 g, 42 mmol) was added and the mixture was stirred at room temperature for 12 hours. The mixture was quenched with water (15 mL) and partitioned between 1N HCl solution (50 mL) and DCM (50 mL). The organic layer was dried over Na ₂ SO ₄ and concentrated in vacuo to give 7.5 g of the title compound. MS (m / z) = 272 (M + H) ^<+> .

(C) 2- (4-Bromophenyl) -2-methylpropane-1,3-diol
To a solution of diethyl 2- (4-bromophenyl) -2-methylmalonate (4.2 g, 12.76 mmol) in dry THF (60 mL) was added LiAlH ₄ (1.06 g, 28.07 mmol) at 0 ° C. The mixture was stirred at 0 ° C. for 3 h before being quenched with water (10 mL) and partitioned between 1N HCl (30 mL) and DCM (100 mL). The organic layer was dried over Na ₂ SO ₄ and concentrated in vacuo to give 3.1 g of the title compound.
¹ H NMR (400 MHz, cdcl ₃ ) δ 7.36-7.32 (m, 2H), 7.31-7.26 (m, 2H), 3.91 (d, J = 11.0, 2H), 3.79 (d, J = 11.0, 2H) , 1.25 (d, J = 0.5, 4H).

(D) 3- (4-Bromophenyl) -3-methyloxetane In a sealed tube, in dry toluene (15 mL), 2- (4-bromophenyl) -2-methylpropane-1,3-diol (3.1 g, 12.76 mmol), PPh ₃ (6.69 g, 25.52 mmol), and DEAD (5.16 g, 25.52 mmol) were mixed and reacted in a microwave at 140 ° C. for 1.5 hours. The mixture was concentrated in vacuo and the residue was purified by flash column chromatography (PE: EA = 1: 0-5: 1) to give 245 mg of the title compound.
¹ H NMR (400 MHz, cdcl ₃ ) δ 7.33-7.31 (m, 2H), 7.15-7.13 (m, 2H), 4.91-4.90 (m, 2H), 4.63-4.61 (m, 2H), 1.70 (s , 3H).

(E) 4,4,5,5-Tetramethyl-2- (4- (3-methyloxetane-3-yl) phenyl) -1,3,2-dioxaborolane The title compound was obtained from intermediate 63 (B). Prepared according to procedure.
¹ H NMR (400 MHz, cdcl ₃ ) δ 7.32-7.30 (m, 2H), 7.15-7.13 (m, 2H), 4.91-4.90 (m, 2H), 4.62-4.61 (m, 2H), 1.70 (s , 3H), 1.25 (s, 12H).

Intermediate 75
2-methyl-2- (4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl) propanoic acid tert-butyl ester

  The title compound was prepared according to the procedure for Intermediate 63.

Intermediate 76
1- (3-Methyl-3- (4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl) azetidin-1-yl) ethanone

(A) 2- (4-Bromophenyl) -2-cyanopropyl 4-methylbenzenesulfonate
To a solution of 2- (4-bromophenyl) -3-hydroxy-2-methylpropanenitrile (1.5 g, 6.25 mmol) and Et ₃ N (1.26 g, 12.5 mmol) in DCM (25 mL) at 0 ° C. TsCl (1.79 g, 9.38 mmol) was added. The mixture was stirred at room temperature overnight and then washed with 1N HCl solution and water. The organic phase was dried over sodium sulfate, filtered and concentrated in vacuo to give 2.5 g of the title compound.
¹ H NMR (400 MHz, cdcl ₃ ) δ 7.66 (d, J = 8.3, 2H), 7.48-7.43 (m, 2H), 7.30 (dd, J = 8.0, 0.6, 2H), 7.25-7.19 (m, 3H), 4.13 (d, J = 1.2, 2H), 2.44 (s, 3H), 1.72 (s, 3H).

(B) 3- (4-Bromophenyl) -3-methylazetidine Under nitrogen, 2- (4-bromophenyl) -2-cyanopropyl 4-methylbenzenesulfonate (2.5 g, 6.25 mmol) in THF (20 mL) To the solution was carefully added LiAlH ₄ (0.28 g, 7.5 mmol) at 0 ° C. The mixture was stirred at room temperature for 2 hours and then treated with aqueous sodium sulfate solution at room temperature for 30 minutes. The mixture was then extracted with DCM and the organic phase was concentrated in vacuo. The residue and K ₂ CO ₃ (1.73 g, 12.5 mmol) were mixed in EtOH (20 mL) and the mixture was stirred at 40 ° C. for 2 hours. This was then filtered and concentrated in vacuo and the residue was purified by column chromatography (MeOH: water = 0: 1 to 10: 1) to give 394 mg of the title compound. MS (m / z): 226 (M + H) ^<+> , 228 (M + 2) ^<+> .

(C) 1- (3- (4-Bromophenyl) -3-methylazetidin-1-yl) ethanone
To a solution of 3- (4-bromophenyl) -3-methylazetidine (200 mg, 0.88 mmol) and Et ₃ N (178 mg, 1.76 mmol) in DCM (10 mL) was added acetyl chloride (104 mg, 1.33 mmol) at 0 ° C. added. After stirring for 1 hour at room temperature, the mixture was concentrated to give the crude product. MS (m / z): 269 (M + H) ^<+> , 270 (M + 2) ^<+> .

(D) 1- (3-Methyl-3- (4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl) azetidin-1-yl) ethanone Title compound Was prepared according to the procedure for intermediate 63 (B).
MS (m / z): 316 (M + H) ^<+> .

Intermediate 77
2- (4-Fluoro-1,1-dimethylisochroman-6-yl) -4,4,5,5-tetramethyl-1,3,2-dioxaborolane

(A) 1,1-dimethyl-4-oxoisochroman-6-yltrifluoromethanesulfonate 1,1-dimethylisochroman-6-yltrifluoromethanesulfonate (1.5 g, 4.83 mmol) and Co (acac) under nitrogen _{To a} solution of ₂ (0.12 g, 0.48 mmol) in dry ACN (30 mL) at 80 ° C. was added t-BuOOH (2.17 g, 24.15 mmol). The mixture was stirred at 80 ° C. for 4 hours. The mixture was then concentrated in vacuo and the residue was purified by column chromatography (PE / EA = 1: 0 to 3: 1) to give 0.24 g of product.
¹ H NMR (400 MHz, cdcl ₃ ) δ 7.87 (d, J = 2.7, 1H), 7.46-7.43 (m, 1H), 7.37-7.33 (m, 1H), 4.45 (d, J = 0.8, 2H) , 1.63 (s, 6H).

(B) 4-hydroxy-1,1-dimethylisochroman-6-yltrifluoromethanesulfonate 1,1-dimethyl-4-oxoisochroman-6-yltrifluoromethanesulfonate (240 mg, 0.74 mmol) in MeOH under nitrogen To the (10 mL) solution was added NaBH ₄ (9 mg, 0.24 mmol) at 0 ° C. The mixture was stirred at 0 ° C. for 1 hour. The mixture was quenched with 1N HCl solution (15 mL) and DCM (50 mL). The organic layer was dried over Na ₂ SO ₄ and concentrated in vacuo to give 250 mg of product.
¹ H NMR (400 MHz, cdcl ₃ ) δ 7.34 (s, 1H), 7.16 (d, J = 1.5, 1H), 4.61-4.50 (m, 1H), 4.04-4.01 (m, 1H), 3.86-3.82 (m, 1H), 2.29 (s, 1H), 1.55 (s, 3H), 1.48 (s, 3H).

(C) 4-Fluoro-1,1-dimethylisochroman-6-yl trifluoromethanesulfonate Drying of 4-hydroxy-1,1-dimethylisochroman-6-yl trifluoromethanesulfonate (250 mg, 0.74 mmol) under nitrogen To a DCM (10 mL) solution was added DAST (120 mg, 0.74 mmol) at 0 ° C. The mixture was stirred at 0 ° C. for 1 hour. The mixture was quenched with 2N NaHCO ₃ solution (30 mL) and DCM (50 mL). The organic layer was dried over Na ₂ SO ₄ and concentrated in vacuo to give 252 mg of the title compound.
¹ H NMR (400 MHz, cdcl ₃ ) δ 7.33 (s, 1H), 7.24-7.23 (m, 1H), 5.43-5.27 (m, 1H), 4.13-4.06 (m, 1H), 4.07-4.02 (m , 1H), 1.58 (s, 3H), 1.48 (s, 3H).

(D) 2- (4-Fluoro-1,1-dimethylisochroman-6-yl) -4,4,5,5-tetramethyl-1,3,2-dioxaborolane The title compound is intermediate 63 (B ).
¹ H NMR (400 MHz, cdcl ₃ ) δ 7.86 (s, 1H), 7.76 (d, J = 7.8, 1H), 7.14 (d, J = 7.8, 1H), 5.39-5.25 (m, 1H), 4.12 -4.07 (m, 2H), 1.57 (s, 3H), 1.45 (s, 3H), 1.32 (s, 12H).

Example 1
Synthetic compounds 1 to 1 to 323
4- (7- (4-morpholinophenyl) pyrido [4,3-b] pyrazin-5-yloxy) cyclohexanol

(A) 4- (7-chloropyrido [4,3-b] pyrazin-5-yloxy) cyclohexanone
Cs ₂ CO ₃ (488 mg, 1.5 mmol) and 5,7-dichloropyrido [4,3-b] pyrazine (200 mg, 1.0 mmol) were added to a dioxane solution of 4-hydroxycyclohexanone (171 mg, 1.5 mmol) at room temperature. It was. The mixture was stirred at 80 ° C. for 18 hours. After 5,7-dichloropyrido [4,3-b] pyrazine was consumed, the reaction mixture was concentrated and the crude was used directly for the next step.

(B) 4- (7- (4-morpholinophenyl) pyrido [4,3-b] pyrazin-5-yloxy) cyclohexanone 4- (7-chloropyrido [4,3-b] pyrazine- from step (A) To a solution of 5-yloxy) cyclohexanone in dioxane / H ₂ O (15 mL / 1.5 mL), Cs ₂ CO ₃ (488.7 mg, 1.5 mmol), Pd (PPh ₃ ) ₄ (231 mg, 0.2 mmol), and 4- (4 -(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl) morpholine (347 mg, 1.2 mmol) was added. The mixture was stirred at 110 ° C. under N ₂ for 24 hours. The reaction mixture was filtered, concentrated and purified by silica gel column chromatography (EA: PE = 2: 1) to give a yellow solid. MS (m / z) = 405 (M + H) ^<+> .

(C) 4- (7- (4-morpholinophenyl) pyrido [4,3-b] pyrazin-5-yloxy) cyclohexanol
4- (7- (4-morpholinophenyl) pyrido [4,3-b] pyrazin-5-yloxy) cyclohexanone (70 mg, 0.17 mmol) in EtOH (5 mL) at −30 ° C. with NaBH ₄ (26 mg, 0.69 mmol) was added in small portions. The mixture was then stirred at −30 ° C. for 20 minutes. When TLC showed that 4- (7- (4-morpholinophenyl) pyrido [4,3-b] pyrazin-5-yloxy) cyclohexanone had disappeared, the reaction solution (maintained cooled) was poured into ice water, Neutralize with 1N HCl solution until pH = 6-7, then extract with EA, wash with brine, dry and concentrate, purify by preparative TLC (DCM: MeOH = 50: 1) The product was then obtained as a yellow solid. MS (m / z) = 407 (M + H) ^<+> .

Compound 2
4- (4- (5- (2- (1H-pyrazol-4-yl) ethoxy) pyrido [3,4-b] pyrazin-7-yl) phenyl) morpholine

(A) 5- (2- (1H-pyrazol-4-yl) ethoxy) -7-chloropyrido [3,4-b] pyrazine The title compound was replaced by 2- (1H-pyrazol-4-yl) ethanol Used and prepared according to the procedure for Compound 1 (A). MS (m / z): 276 (M + H) ^<+> .

(B) 4- (4- (5- (2- (1H-pyrazol-4-yl) ethoxy) pyrido [3,4-b] pyrazin-7-yl) phenyl) morpholine The title compound was compound 1 (B ). MS (m / z): 403 (M + H) ^<+> .

  The following compounds were prepared according to the procedure of Compound 2 using the corresponding intermediates and reagents under appropriate conditions recognized by those skilled in the art.

Compound 3
4- (7- (4-morpholinophenyl) pyrido [4,3-b] pyrazin-5-yloxy) benzamide

(A) Methyl 4- (7-chloropyrido [4,3-b] pyrazin-5-yloxy) benzoate The title compound was prepared according to the procedure for compound 1 (A) using methyl 4-hydroxybenzoate instead. Prepared. MS (m / z): 316 (M + H) ^<+> .

(B) Methyl 4- (7- (4-morpholinophenyl) pyrido [4,3-b] pyrazin-5-yloxy) benzoate 4- (7-chloropyrido [4,4] in dimethoxyethane / water (5 mL) 3-b] pyrazin-5-yloxy) methyl benzoate (340 mg, 1.0 mmol), 4- (4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl ) A mixture of morpholine (347 mg, 1.2 mmol), Pd (dppf) Cl ₂ (73 mg, 0.1 mmol), and Cs ₂ CO ₃ (488 mg, 1.5 mmol) was heated in a microwave reactor at 160 ° C. for 45 minutes. did. The mixture was cooled to room temperature, concentrated and purified by column chromatography (ethyl acetate in petroleum ether from 0% to 100%) and then by a C18 column to give 96 mg of the title compound as a yellow solid. MS (m / z): 443 (M + H) ^<+> .

(C) 4- (7- (4-morpholinophenyl) pyrido [4,3-b] pyrazin-5-yloxy) benzoic acid
To a solution of methyl 4- (7- (4-morpholinophenyl) pyrido [4,3-b] pyrazin-5-yloxy) benzoate (96 mg, 0.22 mmol) in THF (10 mL) was added LiOH H ₂ O (28 mg, 0.66 mmol) in water (5 mL) was added. The mixture was stirred at room temperature overnight. THF was removed in vacuo, the aqueous phase was acidified with 1N HCl to pH = 4, and the resulting acid was extracted with ethyl acetate and dried over anhydrous sodium sulfate. The solvent was removed in vacuo to give 93 mg of the title compound as a yellow solid.

(D) 4- (7- (4-morpholinophenyl) pyrido [4,3-b] pyrazin-5-yloxy) benzamide
4- (7- (4-morpholinophenyl) pyrido [4,3-b] pyrazin-5-yloxy) benzoic acid (93 mg, 0.22 mmol), HATU (103 mg, 0.23 mmol) in THF / dichloromethane (10 mL), A mixture of DIPEA (97 mg, 0.75 mmol) and NH ₄ Cl (24 mg, 0.45 mmol) was stirred at room temperature overnight. The mixture was purified by C18 column chromatography to give 30 mg of the title compound as a yellow solid. MS (m / z): 428 (M + H) ^<+> .

Compound 4
5-(((7- (4-morpholinophenyl) pyrido [3,4-b] pyrazin-5-yl) oxy) methyl) piperidin-2-one

(A) 5-(((7-chloropyrido [3,4-b] pyrazin-5-yl) oxy) methyl) piperidin-2-one The title compound replaces 5- (hydroxymethyl) piperidin-2-one Prepared according to the procedure for compound 1 (A). MS (m / z): 293 (M + H) ^<+> .

(B) 5-((((7- (4-morpholinophenyl) pyrido [3,4-b] pyrazin-5-yl) oxy) methyl) piperidin-2-one The title compound is the procedure for compound 1 (B). Prepared according to MS (m / z): 420 (M + H) ^<+> .

  The following compounds were prepared according to the procedure for Compound 4 using the corresponding intermediates and reagents under appropriate conditions recognized by those skilled in the art.

Compound 6
(S) -2,2-Difluoro-1- (2-((7- (4- (piperazin-1-yl) phenyl) pyrido [4,3-b] pyrazin-5-yloxy) methyl) morpholino) ethanone

(A) (S) -tert-butyl 2-((7-chloropyrido [4,3-b] pyrazin-5-yloxy) methyl) morpholine-4-carboxylate
To a mixture of 5,7-dichloropyrido [4,3-b] pyrazine (2.3 g, 11.51 mmol) and potassium carbonate (4.76 g, 34.52 mmol) in DMF (100 mL) was added (S) -tert-butyl 2- ( Hydroxymethyl) morpholine-4-carboxylate (5.0 g, 23.01 mmol) was added and the mixture was then stirred at 40 ° C. for 72 hours. The solution was poured into water and extracted with EA. The combined organic phases were washed with brine, dried and purified by silica gel chromatography eluting with MeOH / H ₂ O = 1: 1-10: 1 to give 1.83 g of the title compound.

(B) (S) -1- (2-((7-chloropyrido [4,3-b] pyrazin-5-yloxy) methyl) morpholino) -2,2-difluoroethanone
To a solution of (S) -tert-butyl 2-((7-chloropyrido [4,3-b] pyrazin-5-yloxy) methyl) morpholine-4-carboxylate (1.26 g, 3.31 mmol) in EtOAc (20 mL), 5N HCl in EA (5 mL) was added dropwise and then stirred at room temperature for 2 hours. Concentration of the reaction solution gave (S) -2-((7-chloropyrido [4,3-b] pyrazin-5-yloxy) methyl) morpholine hydrochloride as a brown solid that was added to DCM (60 mL). Dissolved. To this stirred solution was added EDCI (1.27 g, 6.62 mmol), HOBT (894 mg, 6.62 mmol), DIPEA (860 mg, 6.62 mmol) and 2,2-difluoroacetic acid (380 mg, 4.0 mmol). After stirring at room temperature overnight, the reaction solution was washed with brine, extracted with DCM and purified by silica gel chromatography eluting with DCM / MeOH = 30: 1 to give the product as a yellow solid. MS (m / z): 359 (M + H) ^<+> .

(C) (S) -2,2-difluoro-1- (2-((7- (4- (piperazin-1-yl) phenyl) pyrido [4,3-b] pyrazin-5-yloxy) methyl) (Morpholino) ethanone (S) -1- (2-((7-chloropyrido [4,3-b] pyrazin-5-yloxy) methyl) morpholino) -2 in dioxane / water (10: 1) (15 mL) , 2-Difluoroethanone (107 mg, 0.3 mmol), 1- (4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl) piperazine hydrochloride (109 mg, Pd (PPh ₃ ) ₄ (69 mg, 0.06 mmol) was added to a mixture of 0.36 mmol) and Cs ₂ CO ₃ (293 mg, 0.9 mmol). The mixture was then heated at 100 ° C. overnight under a nitrogen atmosphere. After cooling, the reaction solution was extracted with EA (100 mL) and washed with brine (50 mL). The organic phase was dried over anhydrous Na ₂ SO ₄ , concentrated and purified by preparative TLC (EA: MeOH = 10: 1) to give the product as a yellow solid. MS (m / z): 485 (M + H) ^<+> .

  The following compounds were prepared according to the procedure of Compound 6 using the corresponding intermediates and reagents under appropriate conditions recognized by those skilled in the art.

Compound 57
(S) -4- (Methylsulfonyl) -2-((7- (4- (1- (methylsulfonyl) piperidin-4-yl) phenyl) pyrido [4,3-b] pyrazin-5-yloxy) methyl Morpholine

(S) -4- (methylsulfonyl) -2-(((7- (4- (piperidin-4-yl) phenyl) pyrido [3,4-b] pyrazin-5-yl) oxy) methyl) morpholine ( To a solution of compound 10) (121.0 mg, 0.25 mmol) and TEA (50 mg, 0.5 mmol) in DCM (3 mL) was added methanesulfonyl chloride (43 mg, 0.375 mmol) and the mixture was stirred at room temperature overnight. The reaction solution was then concentrated, extracted with EA (100 mL), washed with brine (30 mL), dried over anhydrous Na ₂ SO ₄ and purified by preparative TLC (DCM: MeOH = 12: 1). The product was then obtained as an off-white solid. MS (m / z): 562 (M + H) ^<+> .

Compound 58
(S) -2- (4- (4- (5-((4- (methylsulfonyl) morpholin-2-yl) methoxy) pyrido [3,4-b] pyrazin-7-yl) phenyl) piperidine-1 -Il) ethanol

(S) -4- (methylsulfonyl) -2-(((7- (4- (piperidin-4-yl) phenyl) pyrido [3,4-b] pyrazin-5-yl) oxy) methyl) morpholine ( BrCH ₂ CH ₂ OH (58 mg, 0.465) was added dropwise to a DCM (3 mL) solution of compound 10) (75 mg, 0.155 mmol) and TEA (60 mg, 0.62 mmol). The mixture was stirred at room temperature for 4 days. This was then concentrated and EA was added, washed with brine, dried over Na ₂ SO ₄ and purified by preparative TLC (DCM: MeOH = 12: 1) to give the product as a yellow solid. . MS (m / z): 528 (M + H) ^<+> .

  The following compounds were prepared according to the procedure of Compound 58 using the corresponding intermediates and reagents under appropriate conditions recognized by those skilled in the art.

Compound 60
(S) -3- (Dimethylamino) -1- (2-((7- (4-morpholinophenyl) pyrido [4,3-b] pyrazin-5-yloxy) methyl) morpholino) propan-1-one

(A) (S) -tert-butyl 2-((7-chloropyrido [4,3-b] pyrazin-5-yloxy) methyl) morpholine-4-carboxylate
To a solution of 5,7-dichloropyrido [4,3-b] pyrazine (11 g, 55 mmol) in DMF (200 mL), K ₂ CO ₃ (13.8 g, 100 mmol) and (S) -tert-butyl 2- (hydroxymethyl) Morpholine-4-carboxylate (10.86 g, 50 mmol) was added. The mixture was stirred at 40 ° C. for 3 days. The reaction solution was poured into water (600 mL) and extracted with EA (200 mL × 3). The combined organic phases were washed with water (300 mL), brine, concentrated and purified by silica gel column chromatography (EA: PE = 1: 2) to give a white solid. MS (m / z) = 381 (M + H) ^<+> .

(B) (S) -tert-butyl 2-((7- (4-morpholinophenyl) pyrido [4,3-b] pyrazin-5-yloxy) methyl) morpholine-4-carboxylate
(S) -tert-butyl 2-((7-chloropyrido [4,3-b] pyrazin-5-yloxy) methyl) morpholine-4-carboxylate (571 mg, 1.5 mmol) in dioxane / H ₂ O (5 mL / 1.5 mL) solution, Cs ₂ CO ₃ (733 mg, 2.25 mmol), Pd (PPh ₃ ) ₄ (173 mg, 0.15 mmol), and 4- (4- (4,4,5,5-tetramethyl-1, 3,2-Dioxaborolan-2-yl) phenyl) morpholine (492 mg, 1.65 mmol) was added. The mixture was stirred at 100 ° C. under N ₂ for 13 hours. The reaction solution was added to water (100 mL) and extracted with EA. The organic phase was washed with brine and concentrated to give the crude product, which was purified by preparative TLC (DCM: MeOH = 50: 1) to give a yellow solid. MS (m / z) = 508 (M + H) ^<+> .

(C) (S) -2-((7- (4-morpholinophenyl) pyrido [4,3-b] pyrazin-5-yloxy) methyl) morpholine
(S) -tert-butyl 2-((7- (4-morpholinophenyl) pyrido [4,3-b] pyrazin-5-yloxy) methyl) morpholine-4-carboxylate (1.5 mmol) EA (10 mL) Dissolved in a solution of 5N HCl in and stirred at 20 ° C. for 4 hours. The reaction solution was concentrated, washed with saturated NaHCO ₃ (aq), water and brine and concentrated to give a yellow solid. MS (m / z) = 408 (M + H) ^<+> .

(D) (S) -3-Chloro-1- (2-((7- (4-morpholinophenyl) pyrido [4,3-b] pyrazin-5-yloxy) methyl) morpholino) propan-1-one
To a solution of (S) -2-((7- (4-morpholinophenyl) pyrido [4,3-b] pyrazin-5-yloxy) methyl) morpholine (122 mg, 0.3 mmol) in CH ₂ Cl ₂ (5 mL), Et ₃ N (63 uL, 0.45 mmol) and 3-chloropropanoyl chloride (57.2 mg, 0.45 mmol) were added at room temperature. The reaction solution was stirred at room temperature for 4 hours. The reaction solution was then washed with aqueous NaHCO ₃ (5 mL), H ₂ O (5 mL) and brine (5 mL), dried over Na ₂ SO ₄ and concentrated, preparative TLC (CH ₂ Cl ₂ : MeOH = Purification by 50: 1) gave a white solid. MS (m / z) = 498 (M + H) ^<+> .

(E) (S) -3- (Dimethylamino) -1- (2-((7- (4-morpholinophenyl) pyrido [4,3-b] pyrazin-5-yloxy) methyl) morpholino) propane-1 -on
(S) -3-Chloro-1- (2-((7- (4-morpholinophenyl) pyrido [4,3-b] pyrazin-5-yloxy) methyl) morpholino) propan-1-one (111 mg, 0.22 mmol) in dioxane (5 mL) at room temperature were added DIPEA (368 uL, 2.23 mmol) and dimethylamine hydrochloride (182 mg, 2.23 mmol). The reaction solution was sealed and heated at 170 ° C. in a microwave reactor for 0.5 hour. The reaction solution was then concentrated and purified by preparative TLC (CH ₂ Cl ₂ : MeOH = 40: 1) to give a yellow solid. MS (m / z) = 507 (M + H) ^<+> .

  The following compounds were prepared according to the procedure of Compound 60 using the corresponding intermediates and reagents under appropriate conditions recognized by those skilled in the art.

Compound 101
(S) -N, N-dimethyl-4- (5-((4- (2- (2-methyl-1H-imidazol-1-yl) ethylsulfonyl) morpholin-2-yl) methoxy) pyrido [4, 3-b] pyrazin-7-yl) aniline

(A) (S) -tert-butyl 2-((7-chloropyrido [4,3-b] pyrazin-5-yloxy) methyl) morpholine-4-carboxylate The title compound was prepared according to the procedure for compound 60 (A). Prepared. MS (m / z): 381 (M + H) ^<+> .

(B) (S) -tert-butyl 2-((7- (4- (dimethylamino) phenyl) pyrido [4,3-b] pyrazin-5-yloxy) methyl) morpholine-4-carboxylate Prepared according to the procedure for Compound 60 (B). MS (m / z): 466 (M + H) ^<+> .

(C) (S) -N, N-dimethyl-4- (5- (morpholin-2-ylmethoxy) pyrido [4,3-b] pyrazin-7-yl) aniline The title compound of compound 60 (C) Prepared according to procedure. MS (m / z): 366 (M + H) ^<+> .

(D) (S) -N, N-dimethyl-4- (5-((4- (vinylsulfonyl) morpholin-2-yl) methoxy) pyrido [4,3-b] pyrazin-7-yl) aniline
(S) -N, N-dimethyl-4- (5- (morpholin-2-ylmethoxy) pyrido [4,3-b] pyrazin-7-yl) aniline (292.8 mg, 0.8 mmol) in CH ₂ Cl ₂ ( To the solution was added Et ₃ N (278 uL, 2 mmol) and 2-chloroethanesulfonyl chloride (152.4 mg, 1.2 mmol) at room temperature. The reaction solution was stirred at room temperature for 4 hours. The reaction solution was then washed with aqueous NaHCO ₃ (5 mL), H ₂ O (5 mL) and brine (5 mL), dried over Na ₂ SO ₄ and concentrated, preparative TLC (CH ₂ Cl ₂ : MeOH = Purification by 70: 1) gave a white solid. MS (m / z) = 456 (M + H) ^<+> .

(E) (S) -N, N-dimethyl-4- (5-((4- (2- (2-methyl-1H-imidazol-1-yl) ethylsulfonyl) morpholin-2-yl) methoxy) pyrido [4,3-b] pyrazin-7-yl) aniline
(S) -N, N-dimethyl-4- (5-((4- (vinylsulfonyl) morpholin-2-yl) methoxy) pyrido [4,3-b] pyrazin-7-yl) aniline (60 mg, 0.13 mmol) in dioxane (5 mL) at room temperature were added DIPEA (165 uL, 1 mmol) and 2-methyl-1H-imidazole (82.1 mg, 1 mmol). The reaction solution was sealed in a tube and heated at 170 ° C. for 1 hour in a microwave reactor. The reaction solution was then concentrated and purified by preparative TLC (CH ₂ Cl ₂ : MeOH = 40: 1) to give a yellow solid. MS (m / z) = 538 (M + H) ^<+> .

  The following compounds were prepared according to the procedure for Compound 101 using the corresponding intermediates and reagents under appropriate conditions recognized by those skilled in the art.

Compound 115
(S) -N- (2- (2-(((7- (4- (dimethylamino) phenyl) pyrido [3,4-b] pyrazin-5-yl) oxy) methyl) morpholino) ethyl) acetamide

(A) (S) -2- (2- (2-((7- (4- (dimethylamino) phenyl) pyrido [4,3-b] pyrazin-5-yloxy) methyl) morpholino) ethyl) isoindoline 1,3-dione Compound 101 (C) (732 mg, 2 mmol) in DMF (5 mL) was stirred at room temperature with K ₂ CO ₃ (552 mg, 4 mmol) and 2- (2 bromoethyl) isoindoline-1,3-dione (1016 mg, 4 mmol) was added. The reaction was stirred at 100 ° C. for 24 hours. The reaction solution was then extracted with EA, washed with water (5 mL) and brine (5 mL), dried over dry Na ₂ SO ₄ and concentrated, and preparative TLC (CH ₂ Cl ₂ : MeOH = 45: 1 ) To give a solid. MS (m / z) = 539 (M + H) ^<+> .

(B) (S) -4- (5-((4- (2-Aminoethyl) morpholin-2-yl) methoxy) pyrido [4,3-b] pyrazin-7-yl) -N, N-dimethyl Aniline
(S) -2- (2- (2-((7- (4- (dimethylamino) phenyl) pyrido [4,3-b] pyrazin-5-yloxy) methyl) morpholino) ethyl) isoindoline-1, To a solution of 3-dione (279 mg, 0.52 mmol) in ethanol (5 mL) was added 85% N ₂ H ₄ .H ₂ O (52 mg, 1.04 mmol) at room temperature. The mixture was refluxed for 4 hours. The mixture was then adjusted to about PH7 with 2N HCl solution, concentrated and purified by preparative TLC (CH ₂ Cl ₂ : MeOH = 15: 1) to give a yellow solid. MS (m / z) = 409 (M + H) ^<+> .

(C) (S) -N- (2- (2-((7- (4- (dimethylamino) phenyl) pyrido [4,3-b] pyrazin-5-yloxy) methyl) morpholino) ethyl) acetamide
(S) -4- (5-((4- (2-Aminoethyl) morpholin-2-yl) methoxy) pyrido [4,3-b] pyrazin-7-yl) -N, N-dimethylaniline (27 mg , 0.066 mmol) in CH ₂ Cl ₂ (5 mL) at room temperature was added Et ₃ N (14 uL, 0.099 mmol) and acetyl chloride (7.8 mg, 0.099 mmol). The reaction mixture was stirred at room temperature for 4 hours. The reaction mixture was then washed with NaHCO ₃ (5 mL), H ₂ O (5 mL) and brine (5 mL), dried over Na ₂ SO ₄ and concentrated, preparative TLC (CH ₂ Cl ₂ : MeOH = 45 : 1) yielded a yellow solid. MS (m / z) = 451 (M + H) ^<+> .

  The following compounds were prepared according to the procedure for Compound 115 using the corresponding intermediates and reagents under appropriate conditions recognized by those skilled in the art.

Compound 135
((S) -2-(((7- (4- (methylamino) phenyl) pyrido [3,4-b] pyrazin-5-yl) oxy) methyl) morpholino) ((S) -1-methylpyrrolidine -3-yl) methanone

(A) (S) -tert-butyl 2-(((7-chloropyrido [3,4-b] pyrazin-5-yl) oxy) methyl) morpholine-4-carboxylate The title compound is compound 6 (A) Prepared according to the procedure.

(B) (S) -2-(((7-chloropyrido [3,4-b] pyrazin-5-yl) oxy) methyl) morpholine The title compound was prepared according to the procedure for compound 6 (B). MS (m / z): 281 (M + H) ^<+> .

(C) (S) -tert-butyl 3-((S) -2-(((7-chloropyrido [3,4-b] pyrazin-5-yl) oxy) methyl) morpholine-4-carbonyl) pyrrolidine- 1-Carboxylate The title compound was prepared according to the procedure for compound 6 (B).

(D) ((S) -2-(((7-chloropyrido [3,4-b] pyrazin-5-yl) oxy) methyl) morpholino) ((S) -pyrrolidin-3-yl) methanone Prepared according to the procedure for Compound 6 (B). MS (m / z): 378 (M + H) ^<+> .

(E) ((S) -2-(((7-chloropyrido [3,4-b] pyrazin-5-yl) oxy) methyl) morpholino) ((S) -1-methylpyrrolidin-3-yl) methanone
((S) -2-(((7-chloropyrido [3,4-b] pyrazin-5-yl) oxy) methyl) morpholino) ((S) -pyrrolidin-3-yl) methanone (0.43 mmol) Dissolved in% formaldehyde aqueous solution (10 mL) and acetic acid (258 mg, 4.3 mmol). NaOAc (352.6 mg, 4.3 mmol) was added and the mixture was cooled with an ice-water bath. To this mixture was added NaBH ₃ CN (27 mg, 0.43 mmol) and the reaction solution was stirred for 3 hours. Saturated aqueous NaHCO ₃ solution was added until pH> 7. This mixture was extracted twice with DCM. The organic phases were combined, dried over dry MgSO ₄ , concentrated and purified by preparative TLC (DCM: MeOH = 10: 1) to give a yellow solid. MS (m / z) = 392 (M + H) ^<+> .

(F) ((S) -2-(((7- (4- (methylamino) phenyl) pyrido [3,4-b] pyrazin-5-yl) oxy) methyl) morpholino) ((S) -1 -Methylpyrrolidin-3-yl) methanone The title compound was prepared according to the procedure for compound 6 (C). MS (m / z) = 463 (M + H) ^<+> .

Compound 142
(S) -2-(((7- (3,4-Dimethoxyphenyl) pyrido [3,4-b] pyrazin-5-yl) oxy) methyl) morpholine-4-carboxamide

(A) (S) -tert-butyl 2-((7- (3,4-dimethoxyphenyl) pyrido [4,3-b] pyrazin-5-yloxy) methyl) morpholine-4-carboxylate
(S) -tert-butyl 2-((7-chloropyrido [4,3-b] pyrazin-5-yloxy) methyl) morpholine-4-carboxylate (190.4 mg, 0.5 mmol) in dioxane / H ₂ O (5 mL Cs ₂ CO ₃ (244.4 mg, 0.75 mmol), Pd (PPh ₃ ) ₄ (58 mg, 0.05 mmol), and 3,4-dimethoxyphenylboronic acid (100 mg, 0.55 mmol) were added to the solution. . The mixture was sealed in a tube and heated at 160 ° C. for 1 hour in a microwave reactor under N ₂ . The reaction mixture was filtered and the filtrate was concentrated and purified by column chromatography (DCM: MeOH = 70: 1) to give the title compound. MS (m / z) = 483 (M + H) ^<+> .

(B) (S) -2-((7- (3,4-Dimethoxyphenyl) pyrido [4,3-b] pyrazin-5-yloxy) methyl) morpholine
(S) -tert-butyl 2-((7- (3,4-dimethoxyphenyl) pyrido [4,3-b] pyrazin-5-yloxy) methyl) morpholine-4-carboxylate (160 mg, 0.33 mmol) Dissolved in a solution of TFA / CH ₂ Cl ₂ (8 mL / 8 mL) and the mixture was stirred at 20 ° C. for 4 h. The reaction mixture was concentrated and the residue was dissolved in n-BuOH (50 mL). The organic phase was washed with saturated aqueous NaHCO ₃ solution, water, and brine, dried and concentrated to give the title compound. MS (m / z) = 383 (M + H) ^<+> .

(C) (S) -2-((7- (3,4-dimethoxyphenyl) pyrido [4,3-b] pyrazin-5-yloxy) methyl) morpholine-4-carboxamide
(S) -2-((7- (3,4-dimethoxyphenyl) pyrido [4,3-b] pyrazin-5-yloxy) methyl) morpholine (25 mg, 0.065 mmol) in CH ₂ Cl ₂ (5 mL) To this was added Et ₃ N (18 uL, 0.13 mmol) and isocyanatotrimethylsilane (15 mg, 0.13 mmol) at room temperature. The reaction mixture was stirred at room temperature for 20 hours. The reaction solution was then washed with aqueous NaHCO ₃ (5 mL), H ₂ O (5 mL) and brine (5 mL), dried over Na ₂ SO ₄ and concentrated, and thin layer chromatography (CH ₂ Cl ₂ : MeOH). = 30: 1) to give the title compound. MS (m / z) = 426 (M + H) ^<+> .

  The following compounds were prepared according to the procedure of Compound 142 using the corresponding intermediates and reagents under appropriate conditions recognized by those skilled in the art.

Compound 144
(S) -1- (2-(((7- (4- (isopropyl (methyl) amino) phenyl) pyrido [3,4-b] pyrazin-5-yl) oxy) methyl) morpholino) ethanone

化合物141(21mg、0.05mmol)を37%ホルムアルデヒド水溶液(2mL)及び酢酸(30mg、0.5mmol)に溶解した。酢酸ナトリウム(41mg、0.5mmol)を加え、この混合物を氷/水浴中で冷却した。シアノ水素化ホウ素ナトリウム(6.3mg、0.1mmol)を加え、この混合物を3時間撹拌した。混合物が塩基性になるまで、炭酸水素ナトリウム飽和水溶液を加えた。この混合物をDCM(×3)により抽出し、合わせた抽出物を乾燥(MgSO₄)して濃縮し、薄層クロマトグラフィー(CH₂Cl₂:MeOH=40:1)により精製すると、表題化合物が得られた。MS(m/z):436(M+H)⁺。

Compound 141 (21 mg, 0.05 mmol) was dissolved in 37% aqueous formaldehyde (2 mL) and acetic acid (30 mg, 0.5 mmol). Sodium acetate (41 mg, 0.5 mmol) was added and the mixture was cooled in an ice / water bath. Sodium cyanoborohydride (6.3 mg, 0.1 mmol) was added and the mixture was stirred for 3 hours. Saturated aqueous sodium bicarbonate was added until the mixture was basic. The mixture was extracted with DCM (x3) and the combined extracts were dried (MgSO ₄ ), concentrated and purified by thin layer chromatography (CH ₂ Cl ₂ : MeOH = 40: 1) to give the title compound. Obtained. MS (m / z): 436 (M + H) ^<+> .

Compound 199
(S) -Azetidin-1-yl (2-(((7- (4- (dimethylamino) phenyl) pyrido [3,4-b] pyrazin-5-yl) oxy) methyl) morpholino) methanone

(A) (S) -N, N-dimethyl-4- (5- (morpholin-2-ylmethoxy) pyrido [3,4-b] pyrazin-7-yl) aniline The title compound is compound 60 (A)- Prepared according to procedure (C).

(B) (S) -Azetidin-1-yl (2-(((7- (4- (dimethylamino) phenyl) pyrido [3,4-b] pyrazin-5-yl) oxy) methyl) morpholino) methanone To a solution of bis (trichloromethyl) carbonate (71.2 mg, 0.24 mmol) in CH ₂ Cl ₂ (5 mL) at 0 ° C., (S) -N, N-dimethyl-4- (5- (morpholin-2-ylmethoxy) pyrido A solution of [4,3-b] pyrazin-7-yl) aniline (73 mg, 0.2 mmol) and TEA (84 uL, 0.6 mmol) in CH ₂ Cl ₂ (5 mL) was added dropwise. The mixture was stirred at 0 ° C. for 0.5 hour. TLC showed that compound (A) had disappeared, then azetidine was added and the mixture was stirred at 20 ° C. for 18 hours. The reaction mixture was washed with saturated aqueous NaHCO ₃ (5 mL), H ₂ O (5 mL) and brine (5 mL), dried over Na ₂ SO ₄ and concentrated, and thin-layer chromatography (CH ₂ Cl ₂ : MeOH = Purification by 50: 1) gave the title compound. MS (m / z): 449 (M + H) ^<+> .

Compound 206
(S) -4-(((7- (4- (dimethylamino) phenyl) pyrido [3,4-b] pyrazin-5-yl) oxy) methyl) pyrrolidin-2-one

(A) (S) -4-(((7- (4- (dimethylamino) phenyl) pyrido [3,4-b] pyrazin-5-yl) oxy) methyl) -1-((S) -1 -Phenylethyl) pyrrolidin-2-one The title compound was prepared according to the procedure of Compound 2. MS (m / z): 468 (M + H) ^<+> .

(B) (S) -4-(((7- (4- (Dimethylamino) phenyl) pyrido [3,4-b] pyrazin-5-yl) oxy) methyl) pyrrolidin-2-one
(S) -4-(((7- (4- (dimethylamino) phenyl) pyrido [3,4-b] pyrazin-5-yl) oxy) methyl) -1-((S) -1-phenylethyl ) Pyrrolidin-2-one (46.8 mg, 0.1 mmol) was dissolved in TFA (2 mL) in a tube. The tube was sealed and heated in a microwave reactor at 150 ° C. for 75 minutes. The reaction mixture was cooled and concentrated, and the residue was dissolved in DCM (10 mL). The organic phase is washed with saturated aqueous NaHCO ₃ solution, water, and brine, dried and concentrated to give the crude product, which is purified by thin layer chromatography (DCM: MeOH = 40: 1) to give the title compound. was gotten. MS (m / z): 364 (M + H) ^<+> .

  The following compounds were prepared according to the procedure for Compound 206 using the corresponding intermediates and reagents under appropriate conditions recognized by those skilled in the art.

Compound 213
1- (4- (5-(((S) -4- (methylsulfonyl) morpholin-2-yl) methoxy) pyrido [3,4-b] pyrazin-7-yl) phenyl) ethanol

(A) (S) -1- (4- (5-((4- (methylsulfonyl) morpholin-2-yl) methoxy) pyrido [3,4-b] pyrazin-7-yl) phenyl) ethanone Title compound Was prepared according to the procedure of Compound 6. MS (m / z): 443 (M + H) ^<+> .

(B) 1- (4- (5-(((S) -4- (methylsulfonyl) morpholin-2-yl) methoxy) pyrido [3,4-b] pyrazin-7-yl) phenyl) ethanol
(S) -1- (4- (5-((4- (methylsulfonyl) morpholin-2-yl) methoxy) pyrido [3,4-b] pyrazin-7-yl) phenyl) ethanone under N ₂ atmosphere To a solution of (45 mg, 0.10 mmol) in DCM (5 mL) was added DIBAL-H (0.11 mL, 0.11 mmol) at −78 ° C. The mixture was stirred at -78 ° C for 30 minutes. The mixture was quenched with saturated aqueous ammonium chloride (1 mL) and the reaction solution was partitioned between water (10 mL) and DCM (20 mL). The organic phase was dried over Na ₂ SO ₄ and concentrated in vacuo, and the residue was purified by flash column chromatography (MeOH: H ₂ O = 0: 1 to 10: 1) to give 25 mg of the title compound as a white solid. It was. MS (m / z) = 445 (M + H) ^<+> .

Compound 241
(S) -2-(((7- (4- (Tetrahydro-2H-pyran-4-yl) phenyl) pyrido [3,4-b] pyrazin-5-yl) oxy) methyl) morpholine-4-carboxamide

(A) (S) -tert-butyl 2-(((7-chloropyrido [3,4-b] pyrazin-5-yl) oxy) methyl) morpholine-4-carboxylate The title compound was compound 60 (A) Prepared according to the procedure.

(B) (S) -2-(((7-chloropyrido [3,4-b] pyrazin-5-yl) oxy) methyl) morpholine The title compound was prepared according to the procedure for Compound 142 (B). MS (m / z): 281 (M + H) ^<+> .

(C) (S) -2-(((7-chloropyrido [3,4-b] pyrazin-5-yl) oxy) methyl) morpholine-4-carboxamide The title compound was prepared according to the procedure for Compound 142 (C) did. MS (m / z): 324 (M + H) ^<+> .

(D) (S) -2-(((7- (4- (Tetrahydro-2H-pyran-4-yl) phenyl) pyrido [3,4-b] pyrazin-5-yl) oxy) methyl) morpholine The compound was prepared according to the procedure of Compound 142 (A).

(E) (S) -2-(((7- (4- (Tetrahydro-2H-pyran-4-yl) phenyl) pyrido [3,4-b] pyrazin-5-yl) oxy) methyl) morpholine- 4-Carboxamide The title compound was prepared according to the procedure for Compound 142 (C). MS (m / z): 450 (M + H) ^<+> .

  The following compounds were prepared according to the procedure for Compound 241 using the corresponding intermediates and reagents under appropriate conditions recognized by those skilled in the art.

Compound 261
(S) -4-(((7- (4- (1- (methylsulfonyl) piperidin-4-yl) phenyl) pyrido [3,4-b] pyrazin-5-yl) oxy) methyl) pyrrolidine-2 -on

(A) (S) -4-(((7-chloropyrido [3,4-b] pyrazin-5-yl) oxy) methyl) -1-((S) -1-phenylethyl) pyrrolidin-2-one The title compound was prepared according to the procedure for Compound 2 (A). MS (m / z): 383 (M + H) ^<+> .

(B) (S) -4-(((7-chloropyrido [3,4-b] pyrazin-5-yl) oxy) methyl) pyrrolidin-2-one The title compound was prepared according to the procedure for Compound 206 (C) did. MS (m / z): 279 (M + H) ^<+> .

(C) (S) -4-(((7- (4- (1- (methylsulfonyl) piperidin-4-yl) phenyl) pyrido [3,4-b] pyrazin-5-yl) oxy) methyl) Pyrrolidin-2-one The title compound was prepared according to the procedure for Compound 2 (B). MS (m / z): 482 (M + H) ^<+> .

Compound 277
(S) -4- (Methylsulfonyl) -2-(((7- (4- (prop-1-en-2-yl) phenyl) pyrido [3,4-b] pyrazin-5-yl) oxy) Methyl) morpholine

To a solution of compound 219 (25 mg, 0.05 mmol) in DCM (10 mL) at 0 ° C. was added Et ₃ N (22 mg, 0.22 mmol) and methanesulfonic anhydride (20 mg, 0.11 mmol). The mixture was stirred at room temperature for 1 hour. The mixture was concentrated in vacuo and the residue was purified by flash column chromatography (MeOH: H ₂ O = 0: 1 to 10: 1) to give 15 mg of product as a yellow solid. MS (m / z) = 441 (M + H) ^<+> .

Compound 292
(S) -2-(((7- (3,4-Dimethoxyphenyl) pyrido [3,4-b] pyrazin-5-yl) oxy) methyl) morpholine-4-sulfonamide

(A) (S) -tert-butyl 2-(((7-chloropyrido [3,4-b] pyrazin-5-yl) oxy) methyl) morpholine-4-carboxylate The title compound was compound 60 (A) Prepared according to the procedure.

(B) (S) -tert-butyl 2-(((7- (3,4-dimethoxyphenyl) pyrido [3,4-b] pyrazin-5-yl) oxy) methyl) morpholine-4-carboxylate The compound was prepared according to the procedure of Compound 60 (B) using a different catalyst.

(C) (S) -2-(((7- (3,4-dimethoxyphenyl) pyrido [3,4-b] pyrazin-5-yl) oxy) methyl) morpholine The title compound uses different acids Prepared according to the procedure for Compound 60 (C). MS (m / z): 383 (M + H) ^<+> .

(D) (S) -tert-butyl (2-(((7- (3,4-dimethoxyphenyl) pyrido [3,4-b] pyrazin-5-yl) oxy) methyl) morpholino) sulfonylcarbamate
(S) -2-(((7- (3,4-dimethoxyphenyl) pyrido [3,4-b] pyrazin-5-yl) oxy) methyl) morpholine (300 mg, 0.78 mmol) in DCM (3 mL) Dissolved. TEA (315 mg, 3.12 mmol) was added, followed by the slow addition of sulfuryl chloride isocyanate (220 mg, 1.56 mmol). The mixture was stirred at room temperature for 3 hours. Then t-BuOH (2 mL) was added and the mixture was stirred at room temperature overnight. The mixture was concentrated in vacuo and the residue was used directly in the next step.

(E) (S) -2-(((7- (3,4-Dimethoxyphenyl) pyrido [3,4-b] pyrazin-5-yl) oxy) methyl) morpholine-4-sulfonamide
(S) -tert-butyl (2-(((7- (3,4-dimethoxyphenyl) pyrido [3,4-b] pyrazin-5-yl) oxy) methyl) morpholino) sulfonyl in DCM (2 mL) Carbamate (437 mg, 0.78 mmol) was added to CF ₃ COOH (2 mL) and the mixture was stirred at room temperature for 2 hours. The mixture was concentrated in vacuo and the residue was purified by flash column chromatography (DCM / MeOH = 100/100 to 100/10) to give the title product. MS (m / z) = 462 (M + H) ^<+> .

  The following compounds were prepared according to the procedure for Compound 292 using the corresponding intermediates and reagents under appropriate conditions recognized by those skilled in the art.

Compound 295
(S) -1- (2-(((7- (4- (1-acetylazetidin-3-yl) phenyl) pyrido [3,4-b] pyrazin-5-yl) oxy) methyl) morpholino) Ethanon

(A) (S) -tert-butyl 2-(((7- (4- (azetidin-3-yl) phenyl) pyrido [3,4-b] pyrazin-5-yl) oxy) methyl) morpholine-4 -Carboxylate
tert-Butyl 3- (4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl) azetidine-1-carboxylate (0.83 g, 2.3 mmol) was added to acetate ( The mixture was stirred at room temperature for 3 hours until dissolved in 3N HCl in acetate) (15 mL) and TLC indicated that the Boc group was removed. Volatiles were removed in vacuo. (S) -tert-butyl 2-(((7-chloropyrido [3,4-b] pyrazin-5-yl) oxy) methyl) morpholine-4-carboxylate (0.95 g, 2.5 mmol), Pd (dppf) Cl ₂ (169 mg, 0.23 mmol), Cs ₂ CO ₃ (2.25 g, 6.9 mmol), and dioxane / H ₂ O (30 mL / 3 mL) were added. The reaction mixture was heated at 90 ° C. overnight. The mixture was cooled to room temperature, concentrated and purified by silica-gel column chromatography eluting with EtOAc / methanol (gradient) to give 1.03 g of the title compound. MS (m / z): 478 (M + H) ^<+> .

(B) (S) -tert-butyl 2-(((7- (4- (1-acetylazetidin-3-yl) phenyl) pyrido [3,4-b] pyrazin-5-yl) oxy) methyl Morpholine-4-carboxylate
(S) -tert-butyl 2-(((7- (4- (azetidin-3-yl) phenyl) pyrido [3,4-b] pyrazin-5-yl) oxy) methyl) morpholine-4-carboxylate To a solution of (382 mg, 0.80 mmol) in dichloromethane (15 mL) was added triethylamine (242 mg, 2.40 mmol) and acetyl chloride (94 mg, 1.20 mmol). The resulting mixture was stirred at room temperature for 16 hours. The reaction mixture was diluted with dichloromethane (20 mL) and washed with saturated aqueous sodium bicarbonate. The layers were separated and the aqueous layer was further extracted with dichloromethane (15 mL). The combined organic layers were washed with brine, dried (Na ₂ SO ₄ ) and concentrated in vacuo to give 416 mg of product. MS (m / z): 420 (M + H-Boc) ^<+> .

(C) (S) -1- (2-(((7- (4- (1-acetylazetidin-3-yl) phenyl) pyrido [3,4-b] pyrazin-5-yl) oxy) methyl ) Morpholino) Ethanone
(S) -tert-butyl 2-(((7- (4- (1-acetylazetidin-3-yl) phenyl) pyrido [3,4-b] pyrazin-5-yl) oxy) methyl) morpholine- 4-Carboxylate (208 mg, 0.40 mmol) was dissolved in 3N HCl in acetate (15 mL) and the mixture was stirred at room temperature for 1 h until TLC indicated that the Boc group was removed. Volatiles were removed in vacuo and the residue was dissolved in dichloromethane (15 mL). To the resulting solution was added triethylamine (120 mg, 1.20 mmol) and acetyl chloride (47 mg, 0.60 mmol). The resulting mixture was stirred at room temperature for 16 hours. The reaction mixture was concentrated under reduced pressure and purified using _C18 column chromatography to give the title compound as a pale yellow solid. MS (m / z): 462 (M + H) ^<+> .

  The following compounds were prepared according to the procedure for Compound 295 using the corresponding intermediates and reagents under appropriate conditions recognized by those skilled in the art.

Compound 303
(S) -4-Methyl-6-(((7- (4-morpholinophenyl) pyrido [3,4-b] pyrazin-5-yl) oxy) methyl) morpholin-3-one

The title compound was prepared according to the procedure for Compound 60 (B). MS (m / z): 436 (M + H) ^<+> .

  The following compounds were prepared according to the procedure of Compound 303 using the corresponding intermediates and reagents under appropriate conditions recognized by those skilled in the art.

¹ H-NMR data for some compounds are presented.

Example 2
Enzyme assay
SYK enzyme assay:
The Syk kinase assay is performed in vitro using Kit-Tyr 2 Peptide (Invitrogen, catalog number PV3191) in 384 well assay plates. All reactions (40 μL) are 100% DMSO solution, kinase / peptide substrate mixture or phospho-peptide solution (Invitrogen, Cat.No., PV3192, diluted 1.33 × kinase buffer) 10 μL, ATP solution (100 μM) 5 μL or 1.33 × kinase Start by adding 0.8 μL of test compound in buffer (Invitrogen, catalog number, PV3189, diluted 5 × with distilled water), 4.2 μL of distilled water. Mix and incubate the 384-well assay plate (Corning, catalog number 3575) for 1 hour at room temperature. Next, add 10 μL of coloring solution (prepared by diluting coloring reagent A (catalog number, PV3297) 1/32 with coloring buffer (catalog number, PV3127)) to each well, and mix at room temperature. Incubate for 1 hour. The reaction is then stopped by adding 10 μL of stop reagent (Invitrogen, catalog number, PV3094) and reading the plate with a Wallac 1420 VICTOR ³ Multilabel Counter (PerkinElmerTM) with fluorescence at 445 nm and 520 nm. went. All compounds are tested at 8 concentrations (from 1 μM to 0.0003 μM) using a 1: 3 serial dilution scheme.

Below are IC ₅₀ values for some compounds.

VEGFR-2 (KDR) transcreener kinase assay
1. Solution preparation
1) Transcreenen ™ Kinase Assay Kit: Bellbrook Labs., 3003-10K;
2) Recombinant human KDR: Invitrogen, PV3660;
3) Poly E4Y (substrate): Sigma, P0275; 5 mg / mL, dissolved in MilliQ water
4) Assay Buffer: 67mM HEPES, 0.013% TritonX- 100,27mM MgCl 2, 0.67mM MnCl 2, 1.25mM DTT, PH 7.4;
5) 10 mM ATP: Invitrogen, PV3227;
6) 500 mM EDTA: Invitrogen, 15575-038;
7) 96 well black Greiner plate: Greiner, 675076

2. Prepare the solution
1) Maintain the DMSO concentration at 5% and dilute the compound to 5 times the final concentration. This final concentration is 1, 0.33, 0.11, 0.037, 0.012, 0.004, 0.0014, 0.0005 μM, and the final concentration of DMSO is 1%.
2) Prepare the enzyme / substrate stock solution. Both recombinant human KDR and poly E4Y are diluted in assay buffer. These final concentrations are KDR (0.3 ng / μL), poly E4Y (62.5 ng / μL). This mixture is kept on the ice surface before use.
3) Prepare ATP dilution. 10 mM ATP is diluted in assay buffer to a final concentration of 25 μM.
4) Prepare ADP dilution. ADP (500 μM) is diluted in assay buffer, final concentration is 25 μM.
5) Prepare a stock solution for ATP standard curve as follows.

3. Enzymatic reaction
1) Add 5 μL of compound or control (5 μL for 5% DMSO for positive control, 5 μL for 500 mM EDTA for negative control).
2) Add 10 μL of enzyme / substrate stock solution.
3) Add 10 μL of ATP diluted solution to start the enzyme reaction, and mix on a plate shaker.
4) Add 5 μL of 5% DMSO, 10 μL of assay buffer and 10 μL of ATP standard curve stock to standard curve wells.
5) Incubate at 28 ° C for 45 minutes while maintaining gentle shaking on the plate.

4. Stop reaction and detection of ADP
1) Prepare detection mix: ADP Alexa633 tracer (1: 100), ADP antibody (1: 158), and stop / detection buffer (1:10) diluted with MilliQ water.
2) Prepare a tracer-only control: ADP Alexa633 tracer (1: 100), and stop and detect buffer (1:10) diluted in MilliQ water.
3) Prepare control without tracer: Stop and detect buffer (1:10) diluted with MilliQ water.
4) Add 25 μL of detection mix, tracer only control and no tracer control to the corresponding wells.
5) Incubate at 28 ° C for 1 hour while maintaining gentle shaking on the plate.
6) Measure fluorescence polarization (FP) with TECAN F500. Excitation wavelength: 610 nm, emission wavelength: 670 nm.

5. Data analysis

式中、
1) 化合物のウェル[ADP]は、化合物のウェルのADP濃度を表す。
2) 陽性対照のウェル[ADP]は、5%DMSOのウェルのADP濃度を表す。
3) 標準曲線により決定される式に基づいて、mP値をADP濃度に変換する。mP値の測定は、BellBrook Labsによって提供されている説明の提案に従う(www.bellbrooklabs.com)。
IC₅₀: XL-Fit2.0ソフトウェアを使用して算出する。

Where
1) Compound well [ADP] represents the concentration of ADP in the compound well.
2) Positive control well [ADP] represents the ADP concentration of 5% DMSO wells.
3) Convert mP values to ADP concentrations based on the formula determined by the standard curve. The measurement of mP values follows the suggested description provided by BellBrook Labs (www.bellbrooklabs.com).
IC ₅₀ : Calculated using XL-Fit 2.0 software.

Below are IC ₅₀ values for some compounds.

Flt-3 Z-lyte kinase assay:
Raw materials and reagents:

Reaction process
1. Plate map

2. Solution preparation
1) 1.33 x kinase buffer
Dilute the 5 × kinase buffer to 1.33 × with ddH ₂ O.
2) 4 x test compound
Maintain the DMSO concentration at 8% and serially dilute the test compound to 4 times the desired final concentration. This final concentration was 3, 1, 0.33, 0.11, 0.037, 0.012, 0.004, 0.0014 μM, and the final concentration of DMSO was 2%.
3) Kinase / peptide mixture (P / K solution)
A kinase / peptide mixture is prepared by diluting the kinase to 0.12 μg / mL and diluting the Z-LYTE ™ Tyr2 peptide to 4 μM in 1.33 × kinase buffer. Mix gently by pipetting.
4) Phospho-peptide solution (PP solution)
Add 0.4 μL of Z-LYTE ™ Tyr 2 phospho-peptide to 99.6 μL of 1.33 × kinase buffer.
5) ATP solution
Prepare an ATP solution by diluting ATP 10 mM to 1.88 mM in 1.33 × kinase buffer.
6) Coloring solution Dilute Coloring reagent A 1:64 with coloring buffer.

3. Reaction
1) Kinase reaction (volume 10μL)
a. Add 2.5 μL of 4 × test compound to each well except C1, C2, C3 wells.
Add 2.5 μL of 8% DMSO to C1, C2, C3 wells.
b. Place 384 plates on ice.
c. Add 5 μL of P / K mix to each test compound well and C1, C2 wells.
d. Add 5 μL of PP solution to C3 well.
e. Add 2.5 μL of 1.33 × Kinase buffer to C1 and C3 wells.
f. Add 2.5 μL of 4 × ATP solution to each test compound well and C2 well. Shake the plate for 30 seconds and centrifuge (1500 rpm, 1 minute).
g. Seal the plate to protect it from light and incubate the plate at room temperature (25-30 ° C.) for 1 hour.
2) Color reaction
a. Add 5 μL of color solution to all wells.
b. Shake the plate for 30 seconds and centrifuge (1500 rpm, 1 minute).
c. Seal the plate to protect it from light and incubate the plate at room temperature (25-30 ° C.) for 1 hour.
3) Stop and read
Add 5 μL of stop reagent to all wells.
b. Shake the plate for 30 seconds and centrifuge (1500 rpm, 1 minute).
c. Measure the values of coumarin (excitation 400 nm, emission 445 nm) and fluorescein (excitation 400 nm, emission 520 nm), respectively.

4. Data analysis Emission ratio (ER) = luminescence of coumarin (445nm) / luminescence of fluorescein (520nm)
% Phosphorylation = 1- [ER × C3 _520nm -C3 _445nm ] / [(C1 _445nm -C3 _445nm ) + ER × (C3 _520nm -C1 _520nm )]
Inhibition ratio (IR) = 1-% Pho _{test Cpd} /% Pho _C2
IC ₅₀ value: Determined by add-in software for Microsoft Excel, XLfit ™ (version 2.0) from ID Business Solutions (Guildford, UK).

Below are IC ₅₀ values for some compounds.

Example 3
Cell assay
For the determination of IgE-induced beta-hexosaminidase secretion, RBL-2H3 cells (SIBS) are seeded in 96-well plates at 4 × 10 ⁴ cells per well, MEM medium containing 15% FBS and glutamine (2 nM) Incubate for 4 hours and sensitize overnight with 0.5 ug / ml SPE-7. Cells are washed 3 times with Tyrode's buffer and incubated for 20 minutes at 37 ° C., 5% CO ₂ in the presence or absence of various concentrations of test compound. Cells are stimulated by adding 10 uL of DNP-BSA solution (150 ng / mL) to each well and incubated for 45 minutes at 37 ° C., 5% CO ₂ . Next, 45 μL of this supernatant was collected and diluted in 0.05 M citrate buffer (pH 4.5), 100 μL of 1 mM 4-nitrophenyl N-acetyl-β-D-glucosaminide (Sigma, catalog number, N9376) Incubate at 37 ° C for 1.5 hours. The reaction is quenched by adding 185 μL of 0.05M sodium carbonate buffer (pH 10.0). The plate is read on a Multiskan (MK3) at 405 nm.

Below are IC ₅₀ values for some compounds.

Claims (39)

At least one compound of formula (I)

And / or racemic mixtures, enantiomers, diastereomers, tautomers, or mixtures in any ratio, or at least one pharmaceutically acceptable salt or solvate thereof
[Where
R ¹ is hydrogen, halo, -CN, -OH, optionally C ₁ -C ₆ alkyl optionally substituted, optionally C ₁ -C ₆ alkoxy _{substituted, -NH 2, -NH (C 1} ~ C ₄ alkyl), and are independently selected from -N (C ₁ ~C ₄ alkyl) (C ₁ -C ₄ alkyl),
R ² is aryl or heteroaryl, each of which is halo, —NR ⁵ R ⁶ , —OR ⁷ , —S (O) _n R ⁸ , —C (O) R ⁹ , —C (O) OR ⁷ , -CN, -C (O) NR ⁵ R ⁶ , -NR ⁵ C (O) R ⁹ , -NR ⁵ S (O) _n R ⁸ , -NR ⁵ S (O) _n NR ¹⁰ R ¹¹ , -NR ⁵ C (O) OR ⁷ , -NR ⁵ C (O) NR ¹⁰ R ¹¹ , -NO ₂ , -S (O) _n NR ⁵ R ⁶ , optionally substituted lower alkyl, optionally substituted Selected from cycloalkyl, optionally substituted heterocycle, optionally substituted heteroaryl, optionally substituted aryl, optionally substituted alkenyl, and optionally substituted alkynyl. Optionally substituted by one or more groups
L is a C ₁ -C ₆ alkylene substituted by binding or case,
W is cycloalkyl, heterocycle, aryl, or heteroaryl;
R ³ is hydrogen, -Lx-halo, -Lx-R ⁴ , -Lx-NR ⁵ R ⁶ , -Lx-OR ⁷ , -Lx-S (O) _n R ⁸ , -Lx-C (O) R ⁹ , -S (O) _n -Lx-R ⁸ , -C (O) -Lx-R ⁹ , -Lx-CN, -Lx-NR ⁵ C (O) R ⁹ , -Lx-NR ⁵ S (O ) _n R ⁸ , -Lx-NR ⁵ C (O) NR ¹⁰ R ¹¹ , -Lx-NR ⁵ S (O) _n NR ¹⁰ R ¹¹ , -Lx-NR ⁵ C (O) OR ⁷ , -Lx-NR ⁵ S (O) _n OR ⁷ , -NO ₂ , -Lx-C (O) NR ⁵ R ⁶ , -Lx-S (O) _n NR ⁵ R ⁶ , oxo (= O), optionally substituted Independently selected from cycloalkyl, optionally substituted heterocycle, optionally substituted heteroaryl, and optionally substituted aryl,
However, when L is methylene and W is a 5- or 6-membered heterocyclic ring, R ³ is -Lx-NR ⁵ R ⁶ , -Lx-OR ⁷ , -Lx-S (O) _n R ⁸ , -Lx-C (O) R ⁹ , -S (O) _n -Lx-R ⁸ , -C (O) -Lx-R ⁹ , -Lx-CN, -Lx-NR ⁵ C (O) R ⁹ , -Lx-NR ⁵ S (O) _n R ⁸ , -Lx-NR ⁵ C (O) NR ¹⁰ R ¹¹ , -Lx-NR ⁵ S (O) _n NR ¹⁰ R ¹¹ , -Lx-NR ⁵ C (O) OR ⁷ , -Lx-NR ⁵ S (O) _n OR ⁷ , -NO ₂ , -Lx-C (O) NR ⁵ R ⁶ , -Lx-S (O) _n NR ⁵ R ⁶ , oxo ( = O), optionally substituted cycloalkyl, optionally substituted heterocycle, optionally substituted heteroaryl, and optionally substituted aryl. ,
R ⁴ is C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, or C ₂ -C ₆ alkynyl, each of which is optionally substituted;
R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ and R ¹¹ are hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, and heterocycle (each of which, except for hydrogen, halo, -OH, -O (C ₁ ~C _{4 alkyl), - CN, C 1 ~C} 4 _{alkyl, -NH 2, -NH (C 1} ~C 4 _{alkyl), - N (C 1 ~C} 4 alkyl) ( C ₁ -C ₄ alkyl), - C (O) NH 2, -C (O) NH (C 1 ~C 4 alkyl), - C (O) N (C 1 ~C 4 alkyl) (C ₁ -C ₄ alkyl), - C (O) ( C 1 ~C 4 alkyl), - NHC (O) ( C 1 ~C 4 _{alkyl), - N (C 1 ~C} 4 _{alkyl) C (O) (C 1} ~ C _{4 alkyl), - S (O) n} NH 2, -S (O) n NH (C 1 ~C 4 _{alkyl), - S (O) n} n (C 1 ~C 4 alkyl) (C ₁ -C ₄ alkyl), -S (O) _n (C ₁ -C ₄ alkyl), -NHS (O) _n (C ₁ -C ₄ alkyl), -N (C ₁ -C ₄ alkyl) S (O) _n ( C ₁ -C ₄ alkyl), optionally C ₃ -C ₈ cycloalkyl are substituted, and heterocyclic (C ₁ -C ₄ alkyl 3-8 membered optionally substituted is Optionally substituted by one or more groups selected from: optionally substituted by, halo, -OH, -OMe, -CN, or
Or R ⁵ and R ⁶ , R ⁵ and R ⁷ , R ⁵ and R ⁸ , R ⁵ and R ⁹ , and R ⁵ and R ¹⁰ together with the atoms to which they are attached form a ring It can be, the ring, _{halo, -OH, -O (C 1 ~C} 4 _{alkyl), - CN, C 1 ~C} 4 _{alkyl, -NH 2, -NH (C 1} ~C 4 alkyl), - N (C ₁ -C ₄ alkyl) (C ₁ ~C ₄ alkyl), - C (O) NH 2, -C (O) NH (C 1 ~C 4 alkyl), - C (O) N (C 1 ~ C ₄ alkyl) (C ₁ ~C ₄ alkyl), - C (O) ( C 1 ~C 4 alkyl), - NHC (O) ( C 1 ~C 4 _{alkyl), - N (C 1 ~C} 4 alkyl _{) C (O) (C 1} ~C 4 _{alkyl), - S (O) n} NH 2, -S (O) n NH (C 1 ~C 4 _{alkyl), - S (O) n} n (C 1 ~ C ₄ alkyl) (C ₁ ~C _{4 alkyl), - S (O) n} (C 1 ~C 4 _{alkyl), - NHS (O) n} (C 1 ~C 4 alkyl), - n (C ₁ ~C ₄ alkyl) S (O) _n (C ₁ -C ₄ alkyl), optionally substituted C ₃ -C ₈ cycloalkyl, and optionally substituted 3-8 membered heterocycle (C ₁ -C ₄ alkyl is halo, -OH Optionally substituted by one or more groups selected from: optionally substituted by-, --OMe, or --CN;
L _x is a bond or optionally substituted C ₁ -C ₆ alkylene;
m is 0, 1 or 2,
n is 1 or 2,
p is 1, 2 or 3.] R ¹ is hydrogen, halo, -CN, -OH, optionally C ₁ -C ₆ alkyl optionally substituted, optionally C ₁ -C ₆ alkoxy _{substituted, -NH 2, -NH (C 1} ~ C ₄ alkyl), and -N (C ₁ -C ₄ alkyl) (C ₁ -C ₄ alkyl) is independently selected from at least one compound of claim 1, and / or racemic mixtures thereof, An enantiomer, diastereomer, tautomer, or mixture in any ratio, or at least one pharmaceutically acceptable salt or solvate thereof. R ¹ is independently selected from hydrogen, halo, —CN, —OH, or methyl, ethyl, n-propyl, i-propyl, —NH ₂ , N-methylamino, N, N-dimethylamino At least 1 according to claim 2, selected from: N-ethylamino, Nn-propylamino, Ni-propylamino, methoxy, ethoxy, propoxy, isopropoxy, each of which is optionally substituted. Two compounds, and / or racemic mixtures, enantiomers, diastereomers, tautomers, or mixtures of any ratio, or at least one pharmaceutically acceptable salt or solvate thereof. The at least one compound according to claim 3, wherein R ¹ is hydrogen, and / or its racemic mixture, enantiomer, diastereomer, tautomer, or mixture in any ratio, or at least one pharmaceutical agent Acceptable salts or solvates thereof.   5. At least one compound according to any one of claims 1 to 4, wherein m is 1, and / or a racemic mixture, enantiomer, diastereomer, tautomer, or a mixture in any ratio Or at least one pharmaceutically acceptable salt or solvate thereof. R ² is C ₅ -C ₁₀ aryl or 5-10 membered heteroaryl, each of which is halo, —NR ⁵ R ⁶ , —OR ⁷ , —S (O) _n R ⁸ , —C ( O) R ⁹ , -C (O) OR ⁷ , -CN, -C (O) NR ⁵ R ⁶ , -NR ⁵ C (O) R ⁹ , -NR ⁵ S (O) _n R ⁸ , -NR ⁵ S (O) _n NR ¹⁰ R ¹¹ , -NR ⁵ C (O) OR ⁷ , -NR ⁵ C (O) NR ¹⁰ R ¹¹ , -NO ₂ , -S (O) _n NR ⁵ R ⁶ , optionally substituted C ₁ -C ₆ alkyl, optionally substituted C ₃ -C ₈ cycloalkyl, optionally substituted 3-8 membered heterocycle, optionally substituted 5-10 membered heterocycle aryl, optionally substituted C ₅ -C ₁₀ aryl, one or more groups selected from C ₂ -C ₆ alkynyl substituted by C ₂ -C ₆ alkenyl, and optionally substituted optionally Optionally replaced by
R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ and R ¹¹ are hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, and heterocycle (each of which is halo, excluding hydrogen, -OH, -O (C ₁ ~C _{4 alkyl), - CN, C 1 ~C} 4 _{alkyl, -NH 2, -NH (C 1} ~C 4 _{alkyl), - N (C 1 ~C} 4 alkyl) ( C ₁ -C ₄ alkyl), - C (O) NH 2, -C (O) NH (C 1 ~C 4 alkyl), - C (O) N (C 1 ~C 4 alkyl) (C ₁ -C ₄ alkyl), - C (O) ( C 1 ~C 4 alkyl), - NHC (O) ( C 1 ~C 4 _{alkyl), - N (C 1 ~C} 4 _{alkyl) C (O) (C 1} ~ C _{4 alkyl), - S (O) n} NH 2, -S (O) n NH (C 1 ~C 4 _{alkyl), - S (O) n} n (C 1 ~C 4 alkyl) (C ₁ -C ₄ alkyl), -S (O) _n (C ₁ -C ₄ alkyl), -NHS (O) _n (C ₁ -C ₄ alkyl), -N (C ₁ -C ₄ alkyl) S (O) _n ( C ₁ -C ₄ alkyl), optionally C ₃ -C ₈ cycloalkyl are substituted, and heterocyclic (C ₁ -C ₄ alkyl 3-8 membered optionally substituted is Optionally substituted by one or more groups selected from: optionally substituted by, halo, -OH, -OMe, -CN, or
Or R ⁵ and R ⁶ , R ⁵ and R ⁷ , R ⁵ and R ⁸ , R ⁵ and R ⁹ , and R ⁵ and R ¹⁰ together with the atoms to which they are bonded form a ring It can be, the ring, _{halo, -OH, -O (C 1 ~C} 4 _{alkyl), - CN, C 1 ~C} 4 _{alkyl, -NH 2, -NH (C 1} ~C 4 alkyl), - N (C ₁ -C ₄ alkyl) (C ₁ ~C ₄ alkyl), - C (O) NH 2, -C (O) NH (C 1 ~C 4 alkyl), - C (O) N (C 1 ~ C ₄ alkyl) (C ₁ ~C ₄ alkyl), - C (O) ( C 1 ~C 4 alkyl), - NHC (O) ( C 1 ~C 4 _{alkyl), - N (C 1 ~C} 4 alkyl _{) C (O) (C 1} ~C 4 _{alkyl), - S (O) n} NH 2, -S (O) n NH (C 1 ~C 4 _{alkyl), - S (O) n} n (C 1 ~ C ₄ alkyl) (C ₁ ~C _{4 alkyl), - S (O) n} (C 1 ~C 4 _{alkyl), - NHS (O) n} (C 1 ~C 4 alkyl), - n (C ₁ ~C ₄ alkyl) S (O) _n (C ₁ -C ₄ alkyl), optionally substituted C ₃ -C ₈ cycloalkyl, and optionally substituted 3-8 membered heterocycle (C ₁ -C ₄ alkyl is halo, -OH Optionally substituted by one or more groups selected from: optionally substituted by-, --OMe, or --CN,
6. At least one compound according to any one of claims 1 to 5 and / or a racemic mixture, enantiomer, diastereomer, tautomer, or a mixture in any ratio, or at least one pharmaceutical Acceptable salts or solvates thereof. R ² is phenyl, naphthyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, pyrazolyl, imidazolinyl, oxazolyl, isoxazolyl, thiazolyl, thienyl, furyl, benzofuryl, benzothienyl, benzimidazolinyl, indolyl, indazolyl, quinolinyl, and Indanyl, indolinyl, indoline-2-one, 2,3-dihydrobenzofuryl, benzo [d] [1,3] dioxolyl, and 1,2,3,4-tetrahydroquinolinyl, chroman, 2,3-dihydro Benzo [b] [1,4] dioxinyl, 3,4-dihydro-2H-benzo [b] [1,4] oxazinyl, isochroman, 1,3-dihydroisobenzofuryl, 1H-benzo [d] [1, 3] independently selected from oxazine-2 (4H) -onyl, each of which is halo, —NR ⁵ R ⁶ , —OR ⁷ , —S (O) _n R ⁸ , —C (O) R ⁹ , -C (O) OR ⁷ , -CN, -C (O) NR ⁵ R ⁶ , -NR ⁵ C ( O) R ⁹ , -NR ⁵ S (O) _n R ⁸ , -NR ⁵ S (O) _n NR ¹⁰ R ¹¹ , -NR ⁵ C (O) OR ⁷ , -NR ⁵ C (O) NR ¹⁰ R ¹¹ , —NO ₂ , and —S (O) _n NR ⁵ R ⁶ , or methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, and t-butyl, cyclopropyl, Cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, pyrrolidinyl, tetrahydrofuryl, tetrahydropyranyl, piperidinyl, piperazinyl, morpholinyl, homomorpholinyl, thiomorpholinyl, diazepanyl, oxazepanyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrazolidylzolyl , Isoxazolyl, thiazolyl, thienyl, furyl, benzofuryl, benzothienyl, benzimidazolinyl, indolyl, indazolyl, Quinolinyl, phenyl, and naphthyl (each of these is ^{halo, -NR 5 R 6, -OR 7} , -S (O) n R 8, -C (O) R 9, -C (O) OR 7, - CN, -C (O) NR ⁵ R ⁶ , -NR ⁵ C (O) R ⁹ , -NR ⁵ S (O) _n R ⁸ , -NR ⁵ S (O) _n NR ¹⁰ R ¹¹ , -NR ⁵ C (O) OR ⁷ , —NR ⁵ C (O) NR ¹⁰ R ¹¹ , —NO ₂ , —S (O) _n NR ⁵ R ⁶ , optionally substituted lower alkyl, optionally substituted cycloalkyl One or more selected from: an optionally substituted heterocycle, an optionally substituted heteroaryl, an optionally substituted aryl, an optionally substituted alkenyl, and an optionally substituted alkynyl Optionally substituted by one or more groups selected from
R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ and R ¹¹ are hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, and heterocycle (each of which is halo, excluding hydrogen, -OH, -O (C ₁ ~C _{4 alkyl), - CN, C 1 ~C} 4 _{alkyl, -NH 2, -NH (C 1} ~C 4 _{alkyl), - N (C 1 ~C} 4 alkyl) ( C ₁ -C ₄ alkyl), - C (O) NH 2, -C (O) NH (C 1 ~C 4 alkyl), - C (O) N (C 1 ~C 4 alkyl) (C ₁ -C ₄ alkyl), - C (O) ( C 1 ~C 4 alkyl), - NHC (O) ( C 1 ~C 4 _{alkyl), - N (C 1 ~C} 4 _{alkyl) C (O) (C 1} ~ C _{4 alkyl), - S (O) n} NH 2, -S (O) n NH (C 1 ~C 4 _{alkyl), - S (O) n} n (C 1 ~C 4 alkyl) (C ₁ -C ₄ alkyl), -S (O) _n (C ₁ -C ₄ alkyl), -NHS (O) _n (C ₁ -C ₄ alkyl), -N (C ₁ -C ₄ alkyl) S (O) _n ( C ₁ -C ₄ alkyl), optionally C ₃ -C ₈ cycloalkyl are substituted, and heterocyclic (C ₁ -C ₄ alkyl 3-8 membered optionally substituted is Optionally substituted by one or more groups selected from: optionally substituted by, halo, -OH, -OMe, -CN, or
Or R ⁵ and R ⁶ , R ⁵ and R ⁷ , R ⁵ and R ⁸ , R ⁵ and R ⁹ , and R ⁵ and R ¹⁰ together with the atoms to which they are bonded form a ring It can be, the ring, _{halo, -OH, -O (C 1 ~C} 4 _{alkyl), - CN, C 1 ~C} 4 _{alkyl, -NH 2, -NH (C 1} ~C 4 alkyl), - N (C ₁ -C ₄ alkyl) (C ₁ ~C ₄ alkyl), - C (O) NH 2, -C (O) NH (C 1 ~C 4 alkyl), - C (O) N (C 1 ~ C ₄ alkyl) (C ₁ ~C ₄ alkyl), - C (O) ( C 1 ~C 4 alkyl), - NHC (O) ( C 1 ~C 4 _{alkyl), - N (C 1 ~C} 4 alkyl _{) C (O) (C 1} ~C 4 _{alkyl), - S (O) n} NH 2, -S (O) n NH (C 1 ~C 4 _{alkyl), - S (O) n} n (C 1 ~ C ₄ alkyl) (C ₁ ~C _{4 alkyl), - S (O) n} (C 1 ~C 4 _{alkyl), - NHS (O) n} (C 1 ~C 4 alkyl), - n (C ₁ ~C ₄ alkyl) S (O) _n (C ₁ -C ₄ alkyl), optionally substituted C ₃ -C ₈ cycloalkyl, and optionally substituted 3-8 membered heterocycle (C ₁ -C ₄ alkyl is halo, -OH Optionally substituted by one or more groups selected from: optionally substituted by-, --OMe, or --CN,
7. At least one compound according to claim 6 and / or a racemic mixture, enantiomer, diastereomer, tautomer, or any ratio mixture, or at least one pharmaceutically acceptable salt thereof. Or a solvate. R ² is the following formula

Each independently selected from halo, —NR ⁵ R ⁶ , —OR ⁷ , —S (O) _n R ⁸ , —C (O) R ⁹ , —C (O) OR ⁷ , —CN, -C (O) NR ⁵ R ⁶ , -NR ⁵ C (O) R ⁹ , -NR ⁵ S (O) _n R ⁸ , -NR ⁵ S (O) _n NR ¹⁰ R ¹¹ , -NR ⁵ C (O ) OR ⁷ , -NR ⁵ C (O) NR ¹⁰ R ¹¹ , -NO ₂ , and -S (O) _n NR ⁵ R ⁶ , or methyl, ethyl, n-propyl, i-propyl, n -Butyl, i-butyl, and t-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, pyrrolidinyl, tetrahydrofuryl, tetrahydropyranyl, piperidinyl, piperazinyl, morpholinyl, homomorpholinyl, thiomorpholinyl, diazepanyl, oxazepanyl, Pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, pyrazolyl, imidazolinyl, oxazolyl, isoxazolyl, thiazolyl , Thienyl, furyl, benzofuryl, benzothienyl, benzimidazolinyl, indolyl, indazolyl, quinolinyl, phenyl, and naphthyl, each of which is halo, -NR ⁵ R ⁶ , -OR ⁷ , -S (O) _n R ⁸ , -C (O) R ⁹ , -C (O) OR ⁷ , -CN, -C (O) NR ⁵ R ⁶ , -NR ⁵ C (O) R ⁹ , -NR ⁵ S (O) _n R ⁸ , -NR ⁵ S (O) _n NR ¹⁰ R ¹¹ , -NR ⁵ C (O) OR ⁷ , -NR ⁵ C (O) NR ¹⁰ R ¹¹ , -NO ₂ , -S (O) _n NR ⁵ R ⁶ , optionally substituted lower alkyl, optionally substituted cycloalkyl, optionally substituted heterocycle, optionally substituted heteroaryl, optionally substituted aryl, optionally substituted Optionally substituted by one or more groups selected from (optionally substituted by one or more groups selected from alkenyl, and optionally substituted alkynyl). Ri,
R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ and R ¹¹ are hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, and heterocycle (each of which is halo, excluding hydrogen, -OH, -O (C ₁ ~C _{4 alkyl), - CN, C 1 ~C} 4 _{alkyl, -NH 2, -NH (C 1} ~C 4 _{alkyl), - N (C 1 ~C} 4 alkyl) ( C ₁ -C ₄ alkyl), - C (O) NH 2, -C (O) NH (C 1 ~C 4 alkyl), - C (O) N (C 1 ~C 4 alkyl) (C ₁ -C ₄ alkyl), - C (O) ( C 1 ~C 4 alkyl), - NHC (O) ( C 1 ~C 4 _{alkyl), - N (C 1 ~C} 4 _{alkyl) C (O) (C 1} ~ C _{4 alkyl), - S (O) n} NH 2, -S (O) n NH (C 1 ~C 4 _{alkyl), - S (O) n} n (C 1 ~C 4 alkyl) (C ₁ -C ₄ alkyl), -S (O) _n (C ₁ -C ₄ alkyl), -NHS (O) _n (C ₁ -C ₄ alkyl), -N (C ₁ -C ₄ alkyl) S (O) _n ( C ₁ -C ₄ alkyl), optionally C ₃ -C ₈ cycloalkyl are substituted, and heterocyclic (C ₁ -C ₄ alkyl 3-8 membered optionally substituted is Optionally substituted by one or more groups selected from: optionally substituted by, halo, -OH, -OMe, or -CN, or
Or R ⁵ and R ⁶ , R ⁵ and R ⁷ , R ⁵ and R ⁸ , R ⁵ and R ⁹ , and R ⁵ and R ¹⁰ together with the atoms to which they are bonded form a ring It can be, the ring, _{halo, -OH, -O (C 1 ~C} 4 _{alkyl), - CN, C 1 ~C} 4 _{alkyl, -NH 2, -NH (C 1} ~C 4 alkyl), - N (C ₁ -C ₄ alkyl) (C ₁ ~C ₄ alkyl), - C (O) NH 2, -C (O) NH (C 1 ~C 4 alkyl), - C (O) N (C 1 ~ C ₄ alkyl) (C ₁ ~C ₄ alkyl), - C (O) ( C 1 ~C 4 alkyl), - NHC (O) ( C 1 ~C 4 _{alkyl), - N (C 1 ~C} 4 alkyl _{) C (O) (C 1} ~C 4 _{alkyl), - S (O) n} NH 2, -S (O) n NH (C 1 ~C 4 _{alkyl), - S (O) n} n (C 1 ~ C ₄ alkyl) (C ₁ ~C _{4 alkyl), - S (O) n} (C 1 ~C 4 _{alkyl), - NHS (O) n} (C 1 ~C 4 alkyl), - n (C ₁ ~C ₄ alkyl) S (O) _n (C ₁ -C ₄ alkyl), optionally substituted C ₃ -C ₈ cycloalkyl, and optionally substituted 3-8 membered heterocycle (C ₁ -C ₄ alkyl is halo, -OH Optionally substituted by one or more groups selected from: optionally substituted by-, --OMe, or --CN,
8. At least one compound according to claim 7, and / or a racemic mixture, enantiomer, diastereomer, tautomer, or any ratio mixture, or at least one pharmaceutically acceptable salt thereof. Or a solvate. R ² is the following formula

Each independently selected from halo, —NR ⁵ R ⁶ , —OR ⁷ , —S (O) _n R ⁸ , —C (O) R ⁹ , —C (O) OR ⁷ , —CN, -C (O) NR ⁵ R ⁶ , -NR ⁵ C (O) R ⁹ , -NR ⁵ S (O) _n R ⁸ , -NR ⁵ S (O) _n NR ¹⁰ R ¹¹ , -NR ⁵ C (O ) OR ⁷ , -NR ⁵ C (O) NR ¹⁰ R ¹¹ , -NO ₂ , and -S (O) _n NR ⁵ R ⁶ , or methyl, ethyl, n-propyl, i-propyl, n -Butyl, i-butyl, and t-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, pyrrolidinyl, tetrahydrofuryl, tetrahydropyranyl, piperidinyl, piperazinyl, morpholinyl, homomorpholinyl, thiomorpholinyl, diazepanyl, oxazepanyl, Pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, pyrazolyl, imidazolinyl, oxazolyl, isoxazolyl, thiazolyl , Thienyl, furyl, benzofuryl, benzothienyl, benzimidazolinyl, indolyl, indazolyl, quinolinyl, phenyl, and naphthyl, each of which is halo, -NR ⁵ R ⁶ , -OR ⁷ , -S (O) _n R ⁸ , -C (O) R ⁹ , -C (O) OR ⁷ , -CN, -C (O) NR ⁵ R ⁶ , -NR ⁵ C (O) R ⁹ , -NR ⁵ S (O) _n R ⁸ , -NR ⁵ S (O) _n NR ¹⁰ R ¹¹ , -NR ⁵ C (O) OR ⁷ , -NR ⁵ C (O) NR ¹⁰ R ¹¹ , -NO ₂ , -S (O) _n NR ⁵ R ⁶ , optionally substituted lower alkyl, optionally substituted cycloalkyl, optionally substituted heterocycle, optionally substituted heteroaryl, optionally substituted aryl, optionally substituted Optionally substituted by one or more groups selected from (optionally substituted by one or more groups selected from alkenyl, and optionally substituted alkynyl). Ri,
R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ and R ¹¹ are hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, and heterocycle (each of which is halo, excluding hydrogen, -OH, -O (C ₁ ~C _{4 alkyl), - CN, C 1 ~C} 4 _{alkyl, -NH 2, -NH (C 1} ~C 4 _{alkyl), - N (C 1 ~C} 4 alkyl) ( C ₁ -C ₄ alkyl), - C (O) NH 2, -C (O) NH (C 1 ~C 4 alkyl), - C (O) N (C 1 ~C 4 alkyl) (C ₁ -C ₄ alkyl), - C (O) ( C 1 ~C 4 alkyl), - NHC (O) ( C 1 ~C 4 _{alkyl), - N (C 1 ~C} 4 _{alkyl) C (O) (C 1} ~ C _{4 alkyl), - S (O) n} NH 2, -S (O) n NH (C 1 ~C 4 _{alkyl), - S (O) n} n (C 1 ~C 4 alkyl) (C ₁ -C ₄ alkyl), -S (O) _n (C ₁ -C ₄ alkyl), -NHS (O) _n (C ₁ -C ₄ alkyl), -N (C ₁ -C ₄ alkyl) S (O) _n ( C ₁ -C ₄ alkyl), optionally C ₃ -C ₈ cycloalkyl are substituted, and heterocyclic (C ₁ -C ₄ alkyl 3-8 membered optionally substituted is Optionally substituted by one or more groups selected from: optionally substituted by, halo, -OH, -OMe, or -CN, or
Or R ⁵ and R ⁶ , R ⁵ and R ⁷ , R ⁵ and R ⁸ , R ⁵ and R ⁹ , and R ⁵ and R ¹⁰ together with the atoms to which they are bonded form a ring It can be, the ring, _{halo, -OH, -O (C 1 ~C} 4 _{alkyl), - CN, C 1 ~C} 4 _{alkyl, -NH 2, -NH (C 1} ~C 4 alkyl), - N (C ₁ -C ₄ alkyl) (C ₁ ~C ₄ alkyl), - C (O) NH 2, -C (O) NH (C 1 ~C 4 alkyl), - C (O) N (C 1 ~ C ₄ alkyl) (C ₁ ~C ₄ alkyl), - C (O) ( C 1 ~C 4 alkyl), - NHC (O) ( C 1 ~C 4 _{alkyl), - N (C 1 ~C} 4 alkyl _{) C (O) (C 1} ~C 4 _{alkyl), - S (O) n} NH 2, -S (O) n NH (C 1 ~C 4 _{alkyl), - S (O) n} n (C 1 ~ C ₄ alkyl) (C ₁ ~C _{4 alkyl), - S (O) n} (C 1 ~C 4 _{alkyl), - NHS (O) n} (C 1 ~C 4 alkyl), - n (C ₁ ~C ₄ alkyl) S (O) _n (C ₁ -C ₄ alkyl), optionally substituted C ₃ -C ₈ cycloalkyl, and optionally substituted 3-8 membered heterocycle (C ₁ -C ₄ alkyl is halo, -OH Optionally substituted by one or more groups selected from: optionally substituted by-, --OMe, or --CN,
9. At least one compound according to claim 8, and / or a racemic mixture, enantiomer, diastereomer, tautomer, or any ratio mixture, or at least one pharmaceutically acceptable salt thereof. Or a solvate. R ² is the following formula

Each of halo, -NR ⁵ R ⁶ , -OR ⁷ , -S (O) _n R ⁸ , -C (O) R ⁹ , -C (O) OR ⁷ , -CN, -C (O ) NR ⁵ R ⁶ , -NR ⁵ C (O) R ⁹ , -NR ⁵ S (O) _n R ⁸ , -NR ⁵ S (O) _n NR ¹⁰ R ¹¹ , -NR ⁵ C (O) OR ⁷ , Selected from -NR ⁵ C (O) NR ¹⁰ R ¹¹ , -NO ₂ , and -S (O) _n NR ⁵ R ⁶ , or methyl, ethyl, n-propyl, i-propyl, n-butyl, i -Butyl, and t-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, pyrrolidinyl, tetrahydrofuryl, tetrahydropyranyl, piperidinyl, piperazinyl, morpholinyl, homomorpholinyl, thiomorpholinyl, diazepanyl, oxazepanyl, pyridinyl, pyrimidinyl, Pyrazinyl, pyridazinyl, pyrrolyl, pyrazolyl, imidazolinyl, oxazolyl, isoxazolyl, thiazolyl, thienyl, fur Lyl, benzofuryl, benzothienyl, benzimidazolinyl, indolyl, indazolyl, quinolinyl, phenyl, and naphthyl (each of which is halo, -NR ⁵ R ⁶ , -OR ⁷ , -S (O) _n R ⁸ ,- C (O) R ⁹ , -C (O) OR ⁷ , -CN, -C (O) NR ⁵ R ⁶ , -NR ⁵ C (O) R ⁹ , -NR ⁵ S (O) _n R ⁸ ,- NR ⁵ S (O) _n NR ¹⁰ R ¹¹ , -NR ⁵ C (O) OR ⁷ , -NR ⁵ C (O) NR ¹⁰ R ¹¹ , -NO ₂ , -S (O) _n NR ⁵ R ⁶ , Lower alkyl substituted by, optionally substituted cycloalkyl, optionally substituted heterocycle, optionally substituted heteroaryl, optionally substituted aryl, optionally substituted alkenyl And optionally substituted by one or more groups selected from (optionally substituted by one or more groups selected from optionally substituted alkynyl),
R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ and R ¹¹ are hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, and heterocycle (each of which is halo, excluding hydrogen, -OH, -O (C ₁ ~C _{4 alkyl), - CN, C 1 ~C} 4 _{alkyl, -NH 2, -NH (C 1} ~C 4 _{alkyl), - N (C 1 ~C} 4 alkyl) ( C ₁ -C ₄ alkyl), - C (O) NH 2, -C (O) NH (C 1 ~C 4 alkyl), - C (O) N (C 1 ~C 4 alkyl) (C ₁ -C ₄ alkyl), - C (O) ( C 1 ~C 4 alkyl), - NHC (O) ( C 1 ~C 4 _{alkyl), - N (C 1 ~C} 4 _{alkyl) C (O) (C 1} ~ C _{4 alkyl), - S (O) n} NH 2, -S (O) n NH (C 1 ~C 4 _{alkyl), - S (O) n} n (C 1 ~C 4 alkyl) (C ₁ -C ₄ alkyl), -S (O) _n (C ₁ -C ₄ alkyl), -NHS (O) _n (C ₁ -C ₄ alkyl), -N (C ₁ -C ₄ alkyl) S (O) _n ( C ₁ -C ₄ alkyl), optionally C ₃ -C ₈ cycloalkyl are substituted, and heterocyclic (C ₁ -C ₄ alkyl 3-8 membered optionally substituted is Optionally substituted by one or more groups selected from: optionally substituted by, halo, -OH, -OMe, or -CN, or
Or R ⁵ and R ⁶ , R ⁵ and R ⁷ , R ⁵ and R ⁸ , R ⁵ and R ⁹ , and R ⁵ and R ¹⁰ together with the atoms to which they are bonded form a ring It can be, the ring, _{halo, -OH, -O (C 1 ~C} 4 _{alkyl), - CN, C 1 ~C} 4 _{alkyl, -NH 2, -NH (C 1} ~C 4 alkyl), - N (C ₁ -C ₄ alkyl) (C ₁ ~C ₄ alkyl), - C (O) NH 2, -C (O) NH (C 1 ~C 4 alkyl), - C (O) N (C 1 ~ C ₄ alkyl) (C ₁ ~C ₄ alkyl), - C (O) ( C 1 ~C 4 alkyl), - NHC (O) ( C 1 ~C 4 _{alkyl), - N (C 1 ~C} 4 alkyl _{) C (O) (C 1} ~C 4 _{alkyl), - S (O) n} NH 2, -S (O) n NH (C 1 ~C 4 _{alkyl), - S (O) n} n (C 1 ~ C ₄ alkyl) (C ₁ ~C _{4 alkyl), - S (O) n} (C 1 ~C 4 _{alkyl), - NHS (O) n} (C 1 ~C 4 alkyl), - n (C ₁ ~C ₄ alkyl) S (O) _n (C ₁ -C ₄ alkyl), optionally substituted C ₃ -C ₈ cycloalkyl, and optionally substituted 3-8 membered heterocycle (C ₁ -C ₄ alkyl is halo, -OH Optionally substituted by one or more groups selected from: optionally substituted by-, --OMe, or --CN,
10. At least one compound according to claim 9, and / or a racemic mixture, enantiomer, diastereomer, tautomer, or any ratio mixture, or at least one pharmaceutically acceptable salt thereof. Or a solvate. L is a C ₁ -C ₆ alkylene substituted by bond or at least one compound according to any one of claims 1 to 10, and / or racemic mixtures thereof, enantiomers, diastereomers A stereomer, tautomer, or mixture in any ratio, or at least one pharmaceutically acceptable salt or solvate thereof. 12. At least one compound according to claim 11 and / or racemic mixtures, enantiomers, diastereomers, tautomers thereof, wherein L is a bond, or —CH ₂ —, or —CH ₂ —CH ₂ —. Sex, or a mixture in any ratio, or at least one pharmaceutically acceptable salt or solvate thereof. W is, C ₃ -C ₈ cycloalkyl, 3-8 membered heterocyclic ring, heteroaryl of C ₅ -C ₁₀ aryl, or 5-10 membered, according to any one of claims 1 to 12 At least one compound, and / or its racemic mixture, enantiomer, diastereomer, tautomer, or mixture in any ratio, or at least one pharmaceutically acceptable salt or solvate thereof.   W is cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, pyrrolidinyl, tetrahydrofuryl, tetrahydropyranyl, piperidinyl, piperazinyl, morpholinyl, homomorpholinyl, thiomorpholinyl, phenyl, naphthyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl At least one compound according to claim 13, and / or a racemic thereof, which is: Mixture, enantiomer, diastereomer, tautomer, or mixture in any ratio, or at least one pharmaceutical A salt or solvate acceptable.   15.At least one compound according to claim 14 and / or its racemic mixture, enantiomer, diastereomer, tautomer, wherein W is cyclohexyl, tetrahydrofuryl, tetrahydropyranyl, piperidinyl, morpholinyl, phenyl or pyrazolyl. Mutants, or mixtures in any ratio, or at least one pharmaceutically acceptable salt or solvate thereof.   At least one compound of claim 15, and / or racemic mixtures, enantiomers, diastereomers, tautomers, or any ratio thereof, wherein W is tetrahydrofuryl, tetrahydropyranyl, or morpholinyl. Or at least one pharmaceutically acceptable salt or solvate thereof. W is the following formula

At least one compound of claim 16, and / or a racemic mixture, enantiomer, diastereomer, tautomer, or mixture of any ratio, or at least one pharmaceutically acceptable Or a salt or solvate thereof. W is the following formula

At least one compound according to claim 16, and / or a racemic mixture, enantiomer, diastereomer, tautomer thereof (which is substituted on the nitrogen atom by R ³ ) Or a mixture of any ratio, or at least one pharmaceutically acceptable salt or solvate thereof. W is the following formula

At least one compound of claim 16, and / or a racemic mixture, enantiomer, diastereomer, tautomer, or mixture of any ratio, or at least one pharmaceutically acceptable Or a salt or solvate thereof. R ³ is hydrogen, -Lx-halo, -Lx-R ⁴ , -Lx-NR ⁵ R ⁶ , -Lx-OR ⁷ , -Lx-S (O) _n R ⁸ , -Lx-C (O) R ⁹ , -S (O) _n -Lx-R ⁸ , -C (O) -Lx-R ⁹ , -Lx-CN, -Lx-NR ⁵ C (O) R ⁹ , -Lx-NR ⁵ S (O ) _n R ⁸ , -Lx-NR ⁵ C (O) NR ¹⁰ R ¹¹ , -Lx-NR ⁵ S (O) _n NR ¹⁰ R ¹¹ , -Lx-NR ⁵ C (O) OR ⁷ , -Lx-NR ⁵ S (O) _n OR ⁷ , -NO ₂ , -Lx-C (O) NR ⁵ R ⁶ , -Lx-S (O) _n NR ⁵ R ⁶ , oxo (= O), optionally substituted C ₃ -C ₈ cycloalkyl, optionally heterocyclic 3-8 membered substituted, C ₅ -C ₁₀ aryl optionally substituted with, and from 5 to 10 membered heteroaryl which is optionally substituted Independently selected, provided that when L is methylene and W is a 5- or 6-membered heterocycle, R ³ is -Lx-NR ⁵ R ⁶ , -Lx-OR ⁷ ,- Lx-S (O) _n R ⁸ , -Lx-C (O) R ⁹ , -S (O) _n -Lx-R ⁸ , -C (O) -Lx-R ⁹ , -Lx-CN, -Lx -NR ⁵ C (O) R ⁹ , -Lx-NR ⁵ S (O) _n R ⁸ , -Lx-NR ⁵ C (O) NR ¹⁰ R ¹¹ , -Lx-NR ⁵ S (O) _n NR ¹⁰ R ¹¹ , -Lx-NR ⁵ C (O) OR ⁷ , -Lx-NR ⁵ S (O) _n OR ⁷ , -NO ₂ , -Lx-C (O) NR ⁵ R ⁶ , -Lx-S (O) _n NR ⁵ R ⁶ , oxo (= O), optionally substituted From C ₃ -C ₈ cycloalkyl, optionally substituted 3-8 membered heterocycle, optionally substituted C ₅ -C ₁₀ aryl, and optionally substituted 5-10 membered heteroaryl Subject to being independently selected,
R ⁴ is an optionally substituted C ₁ -C ₄ alkyl;
R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ and R ¹¹ are hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, and heterocycle (each of which is halo, excluding hydrogen, -OH, -O (C ₁ ~C _{4 alkyl), - CN, C 1 ~C} 4 _{alkyl, -NH 2, -NH (C 1} ~C 4 _{alkyl), - N (C 1 ~C} 4 alkyl) ( C ₁ -C ₄ alkyl), - C (O) NH 2, -C (O) NH (C 1 ~C 4 alkyl), - C (O) N (C 1 ~C 4 alkyl) (C ₁ -C ₄ alkyl), - C (O) ( C 1 ~C 4 alkyl), - NHC (O) ( C 1 ~C 4 _{alkyl), - N (C 1 ~C} 4 _{alkyl) C (O) (C 1} ~ C _{4 alkyl), - S (O) n} NH 2, -S (O) n NH (C 1 ~C 4 _{alkyl), - S (O) n} n (C 1 ~C 4 alkyl) (C ₁ -C ₄ alkyl), -S (O) _n (C ₁ -C ₄ alkyl), -NHS (O) _n (C ₁ -C ₄ alkyl), -N (C ₁ -C ₄ alkyl) S (O) _n ( C ₁ -C ₄ alkyl), optionally C ₃ -C ₈ cycloalkyl are substituted, and heterocyclic (C ₁ -C ₄ alkyl 3-8 membered optionally substituted is Optionally substituted by one or more groups selected from: optionally substituted by, halo, -OH, -OMe, or -CN, or
Or R ⁵ and R ⁶ , R ⁵ and R ⁷ , R ⁵ and R ⁸ , R ⁵ and R ⁹ , and R ⁵ and R ¹⁰ together with the atoms to which they are bonded form a ring It can be, the ring, _{halo, -OH, -O (C 1 ~C} 4 _{alkyl), - CN, C 1 ~C} 4 _{alkyl, -NH 2, -NH (C 1} ~C 4 alkyl), - N (C ₁ -C ₄ alkyl) (C ₁ ~C ₄ alkyl), - C (O) NH 2, -C (O) NH (C 1 ~C 4 alkyl), - C (O) N (C 1 ~ C ₄ alkyl) (C ₁ ~C ₄ alkyl), - C (O) ( C 1 ~C 4 alkyl), - NHC (O) ( C 1 ~C 4 _{alkyl), - N (C 1 ~C} 4 alkyl _{) C (O) (C 1} ~C 4 _{alkyl), - S (O) n} NH 2, -S (O) n NH (C 1 ~C 4 _{alkyl), - S (O) n} n (C 1 ~ C ₄ alkyl) (C ₁ ~C _{4 alkyl), - S (O) n} (C 1 ~C 4 _{alkyl), - NHS (O) n} (C 1 ~C 4 alkyl), - n (C ₁ ~C ₄ alkyl) S (O) _n (C ₁ -C ₄ alkyl), optionally substituted C ₃ -C ₈ cycloalkyl, and optionally substituted 3-8 membered heterocycle (C ₁ -C ₄ alkyl is halo, -OH Optionally substituted by one or more groups selected from: optionally substituted by-, --OMe, or --CN;
L _x is a bond or optionally substituted C ₁ -C ₆ alkylene,
20.At least one compound according to any one of claims 1 to 19, and / or a racemic mixture, enantiomer, diastereomer, tautomer, or mixture in any ratio, or at least one pharmaceutical Acceptable salts or solvates thereof. R ³ is hydrogen, -Lx-halo, -Lx-R ⁴ , -Lx-NR ⁵ R ⁶ , -Lx-OR ⁷ , -Lx-S (O) _n R ⁸ , -Lx-C (O) R ⁹ , -S (O) _n -Lx-R ⁸ , -C (O) -Lx-R ⁹ , -Lx-CN, -Lx-NR ⁵ C (O) R ⁹ , -Lx-NR ⁵ S (O ) _n R ⁸ , -Lx-NR ⁵ C (O) NR ¹⁰ R ¹¹ , -Lx-NR ⁵ S (O) _n NR ¹⁰ R ¹¹ , -Lx-NR ⁵ C (O) OR ⁷ , -Lx-NR ⁵ S (O) _n OR ⁷ , -NO ₂ , -Lx-C (O) NR ⁵ R ⁶ , -Lx-S (O) _n NR ⁵ R ⁶ , independently selected from oxo (= O) Or cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, pyrrolidinyl, tetrahydrofuryl, tetrahydropyranyl, piperidinyl, piperazinyl, morpholinyl, homomorpholinyl, thiomorpholinyl, diazepanyl, oxazepanyl, phenyl, naphthyl, pyridyl, pyrimidinyl, dipyridinyl , Pyridazinyl, pyrrolyl, pyrazolyl, imidazolinyl, oxazolyl, isoxazoly , Thiazolyl, thienyl, furyl, benzofuryl, benzothienyl, benzimidazolinyl, indolyl, indazolyl, and quinolinyl, each of which is optionally substituted, provided that L is methylene And W is a 5- or 6-membered heterocyclic ring, R ³ is -Lx-NR ⁵ R ⁶ , -Lx-OR ⁷ , -Lx-S (O) _n R ⁸ , -Lx- C (O) R ⁹ , -S (O) _n -Lx-R ⁸ , -C (O) -Lx-R ⁹ , -Lx-CN, -Lx-NR ⁵ C (O) R ⁹ , -Lx- NR ⁵ S (O) _n R ⁸ , -Lx-NR ⁵ C (O) NR ¹⁰ R ¹¹ , -Lx-NR ⁵ S (O) _n NR ¹⁰ R ¹¹ , -Lx-NR ⁵ C (O) OR ⁷ , -Lx-NR ⁵ S (O) _n OR ⁷ , -NO ₂ , -Lx-C (O) NR ⁵ R ⁶ , -Lx-S (O) _n NR ⁵ R ⁶ , independent from oxo (= O) On the condition that
R ⁴ is methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, and t-butyl, each of which is optionally substituted;
R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ and R ¹¹ are hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, and heterocycle (each of which is halo, excluding hydrogen, -OH, -O (C ₁ ~C _{4 alkyl), - CN, C 1 ~C} 4 _{alkyl, -NH 2, -NH (C 1} ~C 4 _{alkyl), - N (C 1 ~C} 4 alkyl) ( C ₁ -C ₄ alkyl), - C (O) NH 2, -C (O) NH (C 1 ~C 4 alkyl), - C (O) N (C 1 ~C 4 alkyl) (C ₁ -C ₄ alkyl), - C (O) ( C 1 ~C 4 alkyl), - NHC (O) ( C 1 ~C 4 _{alkyl), - N (C 1 ~C} 4 _{alkyl) C (O) (C 1} ~ C _{4 alkyl), - S (O) n} NH 2, -S (O) n NH (C 1 ~C 4 _{alkyl), - S (O) n} n (C 1 ~C 4 alkyl) (C ₁ -C ₄ alkyl), -S (O) _n (C ₁ -C ₄ alkyl), -NHS (O) _n (C ₁ -C ₄ alkyl), -N (C ₁ -C ₄ alkyl) S (O) _n ( C ₁ -C ₄ alkyl), optionally C ₃ -C ₈ cycloalkyl are substituted, and heterocyclic (C ₁ -C ₄ alkyl 3-8 membered optionally substituted is Optionally substituted by one or more groups selected from: optionally substituted by, halo, -OH, -OMe, or -CN, or
Or R ⁵ and R ⁶ , R ⁵ and R ⁷ , R ⁵ and R ⁸ , R ⁵ and R ⁹ , and R ⁵ and R ¹⁰ together with the atoms to which they are bonded form a ring It can be, the ring, _{halo, -OH, -O (C 1 ~C} 4 _{alkyl), - CN, C 1 ~C} 4 _{alkyl, -NH 2, -NH (C 1} ~C 4 alkyl), - N (C ₁ -C ₄ alkyl) (C ₁ ~C ₄ alkyl), - C (O) NH 2, -C (O) NH (C 1 ~C 4 alkyl), - C (O) N (C 1 ~ C ₄ alkyl) (C ₁ ~C ₄ alkyl), - C (O) ( C 1 ~C 4 alkyl), - NHC (O) ( C 1 ~C 4 _{alkyl), - N (C 1 ~C} 4 alkyl _{) C (O) (C 1} ~C 4 _{alkyl), - S (O) n} NH 2, -S (O) n NH (C 1 ~C 4 _{alkyl), - S (O) n} n (C 1 ~ C ₄ alkyl) (C ₁ ~C _{4 alkyl), - S (O) n} (C 1 ~C 4 _{alkyl), - NHS (O) n} (C 1 ~C 4 alkyl), - n (C ₁ ~C ₄ alkyl) S (O) _n (C ₁ -C ₄ alkyl), optionally substituted C ₃ -C ₈ cycloalkyl, and optionally substituted 3-8 membered heterocycle (C ₁ -C ₄ alkyl is halo, -OH Optionally substituted by one or more groups selected from: optionally substituted by-, --OMe, or --CN;
L _x is a bond or optionally substituted C ₁ -C ₄ alkylene,
21. At least one compound of claim 20, and / or a racemic mixture, enantiomer, diastereomer, tautomer, or any ratio mixture, or at least one pharmaceutically acceptable salt thereof. Or a solvate. R ³ is hydrogen, -Lx-OR ⁷ , -Lx-S (O) _n R ⁸ , -Lx-C (O) R ⁹ , -S (O) _n -Lx-R ⁸ , -C (O) -Lx-R ⁹ , -Lx-NR ⁵ C (O) R ⁹ , -Lx-NR ⁵ S (O) _n R ⁸ , -Lx-NR ⁵ C (O) NR ¹⁰ R ¹¹ , -Lx-NR ⁵ Independently selected from S (O) _n NR ¹⁰ R ¹¹ , -Lx-C (O) NR ⁵ R ⁶ , -Lx-S (O) _n NR ⁵ R ⁶ , and oxo (= O);
R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ and R ¹¹ are hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, and heterocycle (each of which is halo, excluding hydrogen, -OH, -O (C ₁ ~C _{4 alkyl), - CN, C 1 ~C} 4 _{alkyl, -NH 2, -NH (C 1} ~C 4 _{alkyl), - N (C 1 ~C} 4 alkyl) ( C ₁ -C ₄ alkyl), - C (O) NH 2, -C (O) NH (C 1 ~C 4 alkyl), - C (O) N (C 1 ~C 4 alkyl) (C ₁ -C ₄ alkyl), - C (O) ( C 1 ~C 4 alkyl), - NHC (O) ( C 1 ~C 4 _{alkyl), - N (C 1 ~C} 4 _{alkyl) C (O) (C 1} ~ C _{4 alkyl), - S (O) n} NH 2, -S (O) n NH (C 1 ~C 4 _{alkyl), - S (O) n} n (C 1 ~C 4 alkyl) (C ₁ -C ₄ alkyl), -S (O) _n (C ₁ -C ₄ alkyl), -NHS (O) _n (C ₁ -C ₄ alkyl), -N (C ₁ -C ₄ alkyl) S (O) _n ( C ₁ -C ₄ alkyl), optionally C ₃ -C ₈ cycloalkyl are substituted, and heterocyclic (C ₁ -C ₄ alkyl 3-8 membered optionally substituted is Optionally substituted by one or more groups selected from: optionally substituted by, halo, -OH, -OMe, or -CN, or
Or R ⁵ and R ⁶ , R ⁵ and R ⁷ , R ⁵ and R ⁸ , R ⁵ and R ⁹ , and R ⁵ and R ¹⁰ together with the atoms to which they are bonded form a ring It can be, the ring, _{halo, -OH, -O (C 1 ~C} 4 _{alkyl), - CN, C 1 ~C} 4 _{alkyl, -NH 2, -NH (C 1} ~C 4 alkyl), - N (C ₁ -C ₄ alkyl) (C ₁ ~C ₄ alkyl), - C (O) NH 2, -C (O) NH (C 1 ~C 4 alkyl), - C (O) N (C 1 ~ C ₄ alkyl) (C ₁ ~C ₄ alkyl), - C (O) ( C 1 ~C 4 alkyl), - NHC (O) ( C 1 ~C 4 _{alkyl), - N (C 1 ~C} 4 alkyl _{) C (O) (C 1} ~C 4 _{alkyl), - S (O) n} NH 2, -S (O) n NH (C 1 ~C 4 _{alkyl), - S (O) n} n (C 1 ~ C ₄ alkyl) (C ₁ ~C _{4 alkyl), - S (O) n} (C 1 ~C 4 _{alkyl), - NHS (O) n} (C 1 ~C 4 alkyl), - n (C ₁ ~C ₄ alkyl) S (O) _n (C ₁ -C ₄ alkyl), optionally substituted C ₃ -C ₈ cycloalkyl, and optionally substituted 3-8 membered heterocycle (C ₁ -C ₄ alkyl is halo, -OH Optionally substituted by one or more groups selected from: optionally substituted by-, --OMe, or --CN;
L _x is a bond or optionally substituted C ₁ -C ₄ alkylene,
22. At least one compound according to claim 21, and / or a racemic mixture, enantiomer, diastereomer, tautomer, or mixture in any ratio, or at least one pharmaceutically acceptable salt thereof. Or a solvate. R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ and R ¹¹ are hydrogen, C ₁ -C ₄ alkyl, C ₃ -C ₈ cycloalkyl, C ₅ -C ₁₀ aryl, 5-10 members heteroaryl, and 3-8 membered heterocyclic ring (each of these, with the exception of hydrogen, _{halo, -OH, -O (C 1 ~C} 4 _{alkyl), - CN, C 1 ~C} 4 alkyl, -NH _2, -NH (C ₁ ~C _{4 alkyl), - N (C 1 ~C} 4 alkyl) (C ₁ ~C ₄ alkyl), - C (O) NH 2, -C (O) NH (C 1 ~ C ₄ alkyl), - C (O) N (C 1 ~C 4 alkyl) (C ₁ ~C ₄ alkyl), - C (O) ( C 1 ~C 4 alkyl), - NHC (O) ( C 1 -C _{4 alkyl), - n (C 1 ~C} 4 _{alkyl) C (O) (C 1} ~C 4 _{alkyl), - S (O) n} NH 2, -S (O) n NH (C 1 ~C ₄ alkyl), -S (O) _n N (C ₁ -C ₄ alkyl) (C ₁ -C ₄ alkyl), -S (O) _n (C ₁ -C ₄ alkyl), -NHS (O) _n ( C ₁ -C _{4 alkyl), - n (C 1 ~C} 4 _{alkyl) S (O) n (C} 1 ~C 4 alkyl), when C ₃ -C ₈ cycloalkyl substituted by, and optionally substituted Been 3-8 membered heterocyclic ring that (C ₁ -C ₄ alkyl, halo, -OH, -OMe, or optionally substituted by -CN) optionally substituted by one or more groups selected from At least one compound according to any one of claims 1 to 22 and / or its racemic mixture, enantiomer, diastereomer, tautomer, or A mixture of any ratio, or at least one pharmaceutically acceptable salt or solvate thereof. R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ and R ¹¹ are hydrogen, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, and t-butyl, cyclo Propyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, phenyl, naphthyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, pyrazolyl, imidazolinyl, oxazolyl, isoxazolyl, thiazolyl, thienyl, furyl, benzofuryl, benzothienyl, benzoimidazolyl Nyl, indolyl, indazolyl, quinolinyl, pyrrolidinyl, tetrahydrofuryl, tetrahydropyranyl, piperidinyl, piperazinyl, morpholinyl, homomorpholinyl, thiomorpholinyl, diazepanyl, and oxazepanyl (each except hydrogen _{Halo, -OH, -O (C 1 ~C} 4 _{alkyl), - CN, C 1 ~C} 4 _{alkyl, -NH 2, -NH (C 1} ~C 4 _{alkyl), - N (C 1 ~C} 4 alkyl ) (C ₁ ~C ₄ alkyl), - C (O) NH 2, -C (O) NH (C 1 ~C 4 alkyl), - C (O) N (C 1 ~C 4 alkyl) (C ₁ -C ₄ alkyl), - C (O) ( C 1 ~C 4 alkyl), - NHC (O) ( C 1 ~C 4 _{alkyl), - N (C 1 ~C} 4 alkyl) C (O) (C ₁ -C _{4 alkyl), - S (O) n} NH 2, -S (O) n NH (C 1 ~C 4 _{alkyl), - S (O) n} n (C 1 ~C 4 alkyl) (C ₁ -C _{4 alkyl), - S (O) n} (C 1 ~C 4 _{alkyl), - NHS (O) n} (C 1 ~C 4 _{alkyl), - n (C 1 ~C} 4 alkyl) S (O) _n (C ₁ ~C ₄ alkyl), when the heterocycle (C ₁ -C ₄ alkyl 3- to 8-membered substituted by C ₃ -C ₈ cycloalkyl, and optionally substituted is halo, - Optionally selected from one or more groups selected from (optionally substituted by OH, -OMe, or -CN). At least one compound according to claim 23, and / or its racemic mixture, enantiomer, diastereomer, tautomer, or mixture in any ratio, or at least one pharmaceutically acceptable salt thereof Or a solvate. R ⁵ and R ⁶ , R ⁵ and R ⁷ , R ⁵ and R ⁸ , R ⁵ and R ⁹ , and R ⁵ and R ¹⁰ together with the atoms to which they are bonded can form a ring. can, this ring is _{halo, -OH, -O (C 1 ~C} 4 _{alkyl), - CN, C 1 ~C} 4 _{alkyl, -NH 2, -NH (C 1} ~C 4 alkyl), - N ( C ₁ -C ₄ alkyl) (C ₁ ~C ₄ alkyl), - C (O) NH 2, -C (O) NH (C 1 ~C 4 alkyl), - C (O) N (C 1 ~C ₄ alkyl) (C ₁ -C ₄ alkyl), - C (O) ( C 1 ~C 4 alkyl), - NHC (O) ( C 1 ~C 4 _{alkyl), - N (C 1 ~C} 4 alkyl) _{C (O) (C 1 ~C} 4 _{alkyl), - S (O) n} NH 2, -S (O) n NH (C 1 ~C 4 _{alkyl), - S (O) n} n (C 1 ~C ₄ alkyl) (C ₁ -C _{4 alkyl), - S (O) n} (C 1 ~C 4 _{alkyl), - NHS (O) n} (C 1 ~C 4 _{alkyl), - n (C 1 ~C} 4 _{alkyl) S (O) n (C} 1 ~C 4 alkyl), optionally heterocyclic 3-8 membered substituted by C ₃ -C ₈ cycloalkyl, and optionally substituted (C ₁ -C ₄ Alkyl is halo, -OH, -OM at least one compound according to any one of claims 1 to 22, and / or optionally substituted by one or more groups selected from: Or a racemic mixture, enantiomer, diastereomer, tautomer, or mixture in any ratio, or at least one pharmaceutically acceptable salt or solvate thereof. L _x is a C ₁ -C ₄ alkylene is replaced by a bond or an optionally at least one compound of claim 25, and / or racemic mixtures thereof, enantiomers, diastereomers, tautomers Body, or a mixture of any ratio, or at least one pharmaceutically acceptable salt or solvate thereof.   27.At least one compound according to any one of claims 1 to 26, wherein p is 1 or 2, and / or a racemic mixture, enantiomer, diastereomer, tautomer, or any A mixture of ratios, or at least one pharmaceutically acceptable salt or solvate thereof. R ¹ is independently selected from hydrogen, halo, —CN, —OH, or methyl, ethyl, n-propyl, i-propyl, —NH ₂ , N-methylamino, N, N-dimethylamino , N-ethylamino, Nn-propylamino, Ni-propylamino, methoxy, ethoxy, propoxy, isopropoxy, each of which is optionally substituted,
R ² is phenyl, naphthyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, pyrazolyl, imidazolinyl, oxazolyl, isoxazolyl, thiazolyl, thienyl, furyl, benzofuryl, benzothienyl, benzimidazolinyl, indolyl, indazolyl, quinolinyl, and Indanyl, indolinyl, indoline-2-one, 2,3-dihydrobenzofuryl, benzo [d] [1,3] dioxolyl, and 1,2,3,4-tetrahydroquinolinyl, chroman, 2,3-dihydro Benzo [b] [1,4] dioxinyl, 3,4-dihydro-2H-benzo [b] [1,4] oxazinyl, isochroman, 1,3-dihydroisobenzofuryl, 1H-benzo [d] [1, 3] Oxazine-2 (4H) -onyl (each of which is halo, -NR ⁵ R ⁶ , -OR ⁷ , -S (O) _n R ⁸ , -C (O) R ⁹ , -C (O) OR ⁷ , -CN, -C (O) NR ⁵ R ⁶ , -NR ⁵ C (O) R ⁹ , -NR ⁵ S (O) _n R ⁸ , -NR ⁵ S (O) _n NR ¹⁰ R ¹¹ , -NR ⁵ C (O) OR ⁷ , -NR ⁵ C (O) NR ¹⁰ R ¹¹ , -NO ₂ , and -S (O) _n NR ⁵ R ⁶ Or methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, and t-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, pyrrolidinyl, tetrahydrofuryl, tetrahydro Pyranyl, piperidinyl, piperazinyl, morpholinyl, homomorpholinyl, thiomorpholinyl, diazepanyl, oxazepanyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, pyrazolyl, imidazolinyl, oxazolyl, isoxazolyl, thiazolyl, thienyl, furyl, benzofuryl, thienyl , Indolyl, indazolyl, quinolinyl, phenyl And naphthyl (each of these is ^{halo, -NR 5 R 6, -OR 7} , -S (O) n R 8, -C (O) R 9, -C (O) OR 7, -CN, -C (O) NR ⁵ R ⁶ , -NR ⁵ C (O) R ⁹ , -NR ⁵ S (O) _n R ⁸ , -NR ⁵ S (O) _n NR ¹⁰ R ¹¹ , -NR ⁵ C (O) OR ⁷ , -NR ⁵ C (O) NR ¹⁰ R ¹¹ , -NO ₂ , -S (O) _n NR ⁵ R ⁶ , optionally substituted lower alkyl, optionally substituted cycloalkyl, optionally substituted By one or more groups selected from an optionally substituted heterocycle, an optionally substituted heteroaryl, an optionally substituted aryl, an optionally substituted alkenyl, and an optionally substituted alkynyl Independently selected from) optionally substituted by one or more groups selected from
L is a C ₁ -C ₆ alkylene substituted by binding or case,
W is cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, pyrrolidinyl, tetrahydrofuryl, tetrahydropyranyl, piperidinyl, piperazinyl, morpholinyl, homomorpholinyl, thiomorpholinyl, phenyl, naphthyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl , Pyrazolyl, imidazolinyl, oxazolyl, isoxazolyl, thiazolyl, thienyl, furyl, benzofuryl, benzothienyl, benzoimidazolinyl, indolyl, indazolyl, or quinolinyl,
R ³ is hydrogen, -Lx-halo, -Lx-R ⁴ , -Lx-NR ⁵ R ⁶ , -Lx-OR ⁷ , -Lx-S (O) _n R ⁸ , -Lx-C (O) R ⁹ , -S (O) _n -Lx-R ⁸ , -C (O) -Lx-R ⁹ , -Lx-CN, -Lx-NR ⁵ C (O) R ⁹ , -Lx-NR ⁵ S (O ) _n R ⁸ , -Lx-NR ⁵ C (O) NR ¹⁰ R ¹¹ , -Lx-NR ⁵ S (O) _n NR ¹⁰ R ¹¹ , -Lx-NR ⁵ C (O) OR ⁷ , -Lx-NR Independently selected from ⁵ S (O) nOR ⁷ , -NO ₂ , -Lx-C (O) NR ⁵ R ⁶ , -Lx-S (O) _n NR ⁵ R ⁶ , and oxo (= O) Where L is methylene and W is a 5- or 6-membered heterocyclic ring, R ³ is -Lx-NR ⁵ R ⁶ , -Lx-OR ⁷ , -Lx-S (O) _n R ⁸ , -Lx-C (O) R ⁹ , -S (O) _n -Lx-R ⁸ , -C (O) -Lx-R ⁹ , -Lx-CN, -Lx-NR ⁵ C (O ) R ⁹ , -Lx-NR ⁵ S (O) _n R ⁸ , -Lx-NR ⁵ C (O) NR ¹⁰ R ¹¹ , -Lx-NR ⁵ S (O) _n NR ¹⁰ R ¹¹ , -Lx-NR ⁵ C (O) OR ⁷ , -Lx-NR ⁵ S (O) _n OR ⁷ , -NO ₂ , -Lx-C (O) NR ⁵ R ⁶ , -Lx-S (O) _n NR ⁵ R ⁶ , Provided that it is independently selected from oxo (= O),
R ⁴ is methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, and t-butyl, each of which is optionally substituted;
R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ and R ¹¹ are hydrogen, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, and t-butyl, cyclo Propyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, phenyl, naphthyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, pyrazolyl, imidazolinyl, oxazolyl, isoxazolyl, thiazolyl, thienyl, furyl, benzofuryl, benzothienyl, benzoimidazolyl Nyl, indolyl, indazolyl, quinolinyl, pyrrolidinyl, tetrahydrofuryl, tetrahydropyranyl, piperidinyl, piperazinyl, morpholinyl, homomorpholinyl, thiomorpholinyl, diazepanyl, and oxazepanyl (each except hydrogen _{Halo, -OH, -O (C 1 ~C} 4 _{alkyl), - CN, C 1 ~C} 4 _{alkyl, -NH 2, -NH (C 1} ~C 4 _{alkyl), - N (C 1 ~C} 4 alkyl ) (C ₁ ~C ₄ alkyl), - C (O) NH 2, -C (O) NH (C 1 ~C 4 alkyl), - C (O) N (C 1 ~C 4 alkyl) (C ₁ -C ₄ alkyl), - C (O) ( C 1 ~C 4 alkyl), - NHC (O) ( C 1 ~C 4 _{alkyl), - N (C 1 ~C} 4 alkyl) C (O) (C ₁ -C _{4 alkyl), - S (O) n} NH 2, -S (O) n NH (C 1 ~C 4 _{alkyl), - S (O) n} n (C 1 ~C 4 alkyl) (C ₁ -C _{4 alkyl), - S (O) n} (C 1 ~C 4 _{alkyl), - NHS (O) n} (C 1 ~C 4 _{alkyl), - n (C 1 ~C} 4 alkyl) S (O) _n (C ₁ ~C ₄ alkyl), when the heterocycle (C ₁ -C ₄ alkyl 3- to 8-membered substituted by C ₃ -C ₈ cycloalkyl, and optionally substituted is halo, - Is independently selected from (optionally substituted by one or more groups selected from OH, -OMe, or -CN)
Or R ⁵ and R ⁶ , R ⁵ and R ⁷ , R ⁵ and R ⁸ , R ⁵ and R ⁹ , and R ⁵ and R ¹⁰ together with the atoms to which they are bonded form a ring It can be, the ring, _{halo, -OH, -O (C 1 ~C} 4 _{alkyl), - CN, C 1 ~C} 4 _{alkyl, -NH 2, -NH (C 1} ~C 4 alkyl), - N (C ₁ -C ₄ alkyl) (C ₁ ~C ₄ alkyl), - C (O) NH 2, -C (O) NH (C 1 ~C 4 alkyl), - C (O) N (C 1 ~ C ₄ alkyl) (C ₁ ~C ₄ alkyl), - C (O) ( C 1 ~C 4 alkyl), - NHC (O) ( C 1 ~C 4 _{alkyl), - N (C 1 ~C} 4 alkyl _{) C (O) (C 1} ~C 4 _{alkyl), - S (O) n} NH 2, -S (O) n NH (C 1 ~C 4 _{alkyl), - S (O) n} n (C 1 ~ C ₄ alkyl) (C ₁ ~C _{4 alkyl), - S (O) n} (C 1 ~C 4 _{alkyl), - NHS (O) n} (C 1 ~C 4 alkyl), - n (C ₁ ~C ₄ alkyl) S (O) _n (C ₁ -C ₄ alkyl), optionally substituted C ₃ -C ₈ cycloalkyl, and optionally substituted 3-8 membered heterocycle (C ₁ -C ₄ alkyl is halo, -OH Optionally substituted by one or more groups selected from: optionally substituted by-, --OMe, or --CN;
L _x is a bond or optionally substituted C ₁ -C ₄ alkylene,
m is 0, 1 or 2;
n is 1 or 2,
p is 1, 2 or 3;
At least one compound of formula (I) according to claim 1 and / or a racemic mixture, enantiomer, diastereomer, tautomer, or mixture in any ratio, or at least one pharmaceutically An acceptable salt or solvate thereof. The optionally substituted lower alkyl is —CF ₃ , —CF ₂ H, —CH ₂ NH ₂ , —CH ₂ CH ₂ NH ₂ , —CH ₂ OH, —CH ₂ CH ₂ OH, —CH ₂ OCH ₃ At least one compound according to any one of claims 1 to 28, and / or a racemic mixture, enantiomer, diastereomer, tautomer thereof, selected from: -CH ₂ CH ₂ OCH ₃ Or a mixture of any ratio, or at least one pharmaceutically acceptable salt or solvate thereof.   At least one compound selected from compounds 1 to 323, and / or racemic mixtures, enantiomers, diastereomers, tautomers, or mixtures of any ratio, or at least one pharmaceutically acceptable thereof Its salt or solvate.   At least one compound according to any one of claims 1 to 30, and / or a racemic mixture, enantiomer, diastereomer, tautomer, or mixture in any ratio, or at least one pharmaceutical A composition comprising a pharmaceutically acceptable salt or solvate thereof and at least one pharmaceutically acceptable carrier.   A pharmaceutical composition for treating a Syk kinase mediated disease comprising a therapeutically effective amount of a compound of formula (I) according to any one of claims 1 to 31 and a pharmaceutically acceptable excipient. .   32. A medicament for treating a Syk kinase mediated disease comprising a therapeutically effective amount of a compound of formula (I) according to any one of claims 1-31.   32. Use of a compound of formula (I) according to any one of claims 1 to 31 in the manufacture of a medicament for treating a Syk mediated disease in a subject in need thereof.   32. A method of inhibiting Syk kinase comprising administering to a system or subject in need thereof a therapeutically effective amount of a compound of formula (I) according to any one of claims 1-31.   32. A method of treating a Syk mediated disease comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula (I) according to any one of claims 1-31.   37. The method of claim 36, wherein the disease is an inflammatory disease, allergic disease, cell proliferative disease, autoimmune disease, or cytopenia.   Diseases are allergic asthma, allergic rhinitis, rheumatoid arthritis, multiple sclerosis, lupus, systemic lupus erythematosus, lymphoma, B cell lymphoma, T cell lymphoma, leukemia, myelodysplastic syndrome, anemia, leukopenia, neutrophil 38. The method of claim 37, wherein the method is cytopenia, thrombocytopenia, granulocytopenia, pancytopenia, or idiopathic thrombocytopenic purpura.   A compound for use in a method of medical treatment, wherein the method of medical treatment is for treating a Syk kinase mediated disease, wherein the disease is allergic asthma, allergic rhinitis, rheumatoid arthritis, Multiple sclerosis, lupus, systemic lupus lupus erythematosus, lymphoma, B cell lymphoma, T cell lymphoma, leukemia, myelodysplastic syndrome, anemia, leukopenia, neutropenia, thrombocytopenia, granulocytopenia, pancytopenia 32. A compound of formula (I) according to any one of claims 1 to 31 which is idiopathic thrombocytopenic purpura.